tbuckley/cabot-search huggingface dataset:
Contribution of Volume Overload and Angiotensin II to the Increased Pulse Wave Velocity of Hemodialysis Patients
Authors: J. L. Tycho Vuurmans, Walther H. Boer, Willem-Jan W. Bos, Peter J. Blankestijn, Hein A. Koomans
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Aortic compliance is decreased in patients with end-stage renal disease. This malfunction contributes to high aortic systolic pressures and thus to the development of left ventricular hypertrophy. It was hypothesized that besides structural vascular changes, functional changes as a result of hypervolemia and increased vasoconstrictor activity, in particular angiotensin II, play a role in decreasing aortic compliance. Nineteen hemodialysis patients were studied before and 24 h after they had been dialyzed to dry weight. Applanation tonometry of peripheral arteries was used to estimate aortic pulse wave velocity (PWV), known to depend on aortic compliance, and aortic systolic pressure augmentation (augmentation index [Aix]). Predialysis aortic PWV was increased in the dialysis patients compared with matched healthy subjects (9.9 ± 3.1 versus 7.5 ± 1.1 m/s; P < 0.05). The AIx was also increased (35 ± 6 versus 25 ± 10; P < 0.05). Volume reduction with dialysis had no significant effect on PWV (9.3 ± 1.5 m/s), but the AIx decreased (28 ± 7; P < 0.05). A subset of 10 patients were restudied after 1 wk of angiotensin-converting enzyme inhibition (ACEi) with enalapril 5 mg once daily. ACEi decreased both predialysis as postdialysis BP but had no effect on pulse pressure and heart rate, which remained elevated compared with healthy subjects. ACEi also decreased predialysis aortic PWV, from 11.0 ± 3.5 to 9.1 ± 2.1 m/s (P < 0.05) but had no significant effect on AIx. During treatment with ACEi, the same volume reduction with dialysis decreased aortic PWV further to 8.0 ± 1.4 m/s (P < 0.05), a figure not different from PWV in healthy subjects. AIx decreased to an even slightly subnormal value (12 ± 23; P < 0.05). It was concluded that volume overload and angiotensin II both contribute to elevated PWV and AIx in dialysis patients. Volume reduction and ACEi both improve the aortic PWV and AIx. Combined volume reduction and ACEi has an enhanced effect that, in the present patients, was so large that PWV and AIx were no longer elevated. Monitoring and correcting of arterial pressure waves is feasible and may be an important tool in the treatment of patients with end-stage renal disease.
Sample size for a phylogenetic inference.
Authors: G A Churchill, A von Haeseler, W C Navidi
Journal: Molecular Biology and Evolution (1992)

The objective of this work is to describe sample-size calculations for the inference of a nonzero central branch length in an unrooted four-species phylogeny. Attention is restricted to independent binary characters, such as might be obtained from an alignment of the purine-pyrimidine sequences of a nucleic acid molecule. A statistical test based on a multinomial model for character-state configurations is described. The importance of including invariable sites in models for sequence change is demonstrated, and their effect on sample size is quantified. The methods are applied to a four-species alignment of small-subunit rRNA sequences derived from two archaebacteria, a eubacteria and a eukaryote. We conclude that the information in these sequences is not sufficient to resolve the branching order of this tree. Estimates of the number of aligned nucleotide positions required to provide a reasonably powerful test are given.
Passive smoking and sudden infant death syndrome: review of the epidemiological evidence
Authors: H. R. Anderson, D. G. Cook
Journal: Thorax (1997)

<h3>Abstract</h3> Lower function of the serotonin transporter (5-HTT) has a strong relationship with the development of autism spectrum disorder (ASD) in humans. One characteristic of ASD is the repetitive and restrictive behavior, which may form the basis for better memory and savant skills in some people with ASD. This characteristic in ASD may reflect a tendency towards an exploitation strategy rather than an exploration strategy during learning. Using a rat model, we developed a touchscreen-based task for testing 5-HTT knockout effects on stimulus category learning. By analyzing the data with a reinforcement learning drift diffusion model, we find that 5-HTT knockout rats show a lower learning rate and apply more of an exploitation versus exploration strategy compared to WT rats during category learning. The decision bound of decision-making during stimulus generalization indicates that more 5-HTT knockout rats than WT rats exploit irrelevant information to categorize stimuli. The touchscreen-based task we developed greatly increases the translational value from animals to humans and helps to understand the behavioral mechanisms underlying repetitive behavior in ASD.
PHYSIOLOGICAL FACTORS AFFECTING AIRWAY RESISTANCE IN NORMAL SUBJECTS AND IN PATIENTS WITH OBSTRUCTIVE RESPIRATORY DISEASE*
Authors: John Butler, Colin G. Caro, Raphael Alcala, Arthur B. DuBois
Journal: Journal of Clinical Investigation (1960)

Although the airway conductance1 increases at larger lung volumes in normal subjects (1), it is reduced in patients with asthma or emphysema who are breathing with a large functional residual capacity (FRC) (2).We have therefore tried to assess the influence of other factors which might affect the airway conductance in both normal sub- jects and in patients with asthma, bronchitis and emphysema.These include the interrelationship of lung volume, lung elastic pressure and airway conductance, the effect of exercise, forced breath- ing and normal aging, and the composition of the respired gas and bronchomotor drugs.We in- vestigated the balance of forces regulating the di- ameter of the airway lumen, i.e., the tone of the airway wall, directed inward, opposed by the traction of the lung tissues, directed outward.We studied whether, in normal subjects, this balance was altered by bronchmotor drugs or by a change in lung elastic pressure following chest strapping, and whether in patients with asthma, the airway conductance/lung volume relationship was altered after forced breathing or exercise.Patterns of disturbance leading to air trapping
Proliferative arrest and rapid turnover of thymic epithelial cells expressing Aire
Authors: Daniel Gray, Jakub Abramson, Christophe Benoist, Diane Mathis
Journal: The Journal of Experimental Medicine (2007)

Expression of autoimmune regulator (Aire) by thymic medullary epithelial cells (MECs) is critical for central tolerance of self. To explore the mechanism by which such a rare cell population imposes tolerance on the large repertoire of differentiating thymocytes, we examined the proliferation and turnover of Aire(+) and Aire(-) MEC subsets through flow cytometric analysis of 5-bromo-2'deoxyuridine (BrdU) incorporation. The Aire(+) MEC subset was almost entirely postmitotic and derived from cycling Aire(-) precursors. Experiments using reaggregate thymic organ cultures revealed the presence of such precursors among Aire(-) MECs expressing low levels of major histocompatibility complex class II and CD80. The kinetics of BrdU decay showed the Aire(+) population to have a high turnover. Aire did not have a direct impact on the division of MECs in vitro or in vivo but, rather, induced their apoptosis. We argue that these properties strongly favor a "terminal differentiation" model for Aire function in MECs, placing strict temporal limits on the operation of any individual Aire(+) MEC in central tolerance induction. We further speculate that the speedy apoptosis of Aire-expressing MECs may be a mechanism to promote cross-presentation of the array of peripheral-tissue antigens they produce.
Macrophage activation selectively enhances expression of Fc receptors for IgG2a.
Authors: R A Ezekowitz, M Bampton, S Gordon
Journal: The Journal of Experimental Medicine (1983)

After infection with bacillus Calmette-Guérin, peritoneal macrophages (Mø) display enhanced expression of FcR for both monomeric and complexed IgG2a, but not IgG2b. Isotype specificity of FcR can be reversed on nonactivated Mø by immune lymphokines, and IgG2a immune complexes are more effective triggers of the respiratory burst in activated Mø. Selective enhancement of IgG2a FcR by Mø activation could account for efficacy of homologous ab in mediating cytotoxicity in some systems.
Nutritional zinc increases platelet reactivity
Authors: Gerard Marx, Judit Krugliak, Matityahu Shaklai
Journal: American Journal of Hematology (1991)

Abstract After ingestion of 220 mg zinc sulfate, platelet aggregation was evaluated at various time intervals (i.e., T = 0, 1, and 3 hr) and the autologous plasma analyzed by atomic absorption analysis. The zinc levels increased maximally some 0.4 ± 0.2 μg/ml within 3 hr after ingestion, which tor the entire blood pool corresponds to only 5% of the ingested zinc. Aggregation responses of platelet rich plasma (PRP), instigated with suboptimal levels of thrombin (&lt;0.2 U/ml), ADP (&lt;2 μM), epinephrine (&lt;2 μM), collagen (&lt;2 μg/ml), or PAF (&lt;50 ng/ml), show significant improvement to at least one aggregant. Mean ± SEM values for Δ% aggregation increase are as follows: thrombin, 51 ± 10%; epinephrine, 21 ± 6%; ADP, 31 ± 6%; collagen 23 ± 6%; and platelet aggregating factor (PAF), 56 ± 6%. For controls, the platelets from one individual with Glanzmann thrombasthenia as well as four undosed volunteers exhibited no significant changes in platelet responsiveness. Increased platelet responsiveness to agonists after zinc sulfate ingestion was observed in PRP from blood collected in either citrate or heparin. We demonstrate that within a relatively short time period, single bolus of nutritional zinc intake can significantly increase platelet reactivity. These findings show that nutritional zinc availability is relevant to hemostasis and may pertain to the viability of platelet concentrates in blood banks.
Decreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells
Authors: David M. Kofler, Alexander Marson, Margarita Dominguez-Villar, Sheng Xiao, Vijay K. Kuchroo, David A. Hafler
Journal: Journal of Clinical Investigation (2014)

Prostaglandin E2 (PGE2) promotes Th17 expansion while otherwise inhibiting other CD4+ T cell subsets. Here, we identified a PGE2-dependent pathway that induces pathogenic Th17 cells in autoimmune disease and is regulated by the transcription factor RORC. Compared with other CD4+ cell types from healthy subjects, there is a surprising lack of the prostaglandin receptor EP2 on Th17 cells; therefore, we examined the hypothesis that RORγt, which is highly expressed in Th17 cells, mediates EP2 downregulation. Chromatin immunoprecipitation followed by DNA sequencing revealed that RORγt binds directly to Ptger2 (the gene encoding EP2 receptor) in Th17 cells isolated from WT mice. In Th17 cells isolated from humans, RORC repressed EP2 by directly silencing PTGER2 transcription, and knock down of RORC restored EP2 expression in Th17 cells. Compared with Th17 cells from healthy individuals, Th17 cells from patients with MS exhibited reduced RORC binding to the PTGER2 promoter region, resulting in higher EP2 levels and increased expression of IFN-γ and GM-CSF. Finally, overexpression of EP2 in Th17 cells from healthy individuals induced a specific program of inflammatory gene transcription that produced a pathogenic Th17 cell phenotype. These findings reveal that RORC directly regulates the effects of PGE2 on Th17 cells, and dysfunction of this pathway induces a pathogenic Th17 cell phenotype.
Effects of Valsartan on Circulating Brain Natriuretic Peptide and Norepinephrine in Symptomatic Chronic Heart Failure
Authors: Roberto Latini, Serge Masson, Inder Anand, Dianne Judd, Aldo P. Maggioni, Yann-Tong Chiang, Maurizio Bevilacqua, Monica Salio, Paola Cardano, Peter H.J.M. Dunselman, Nicolaas J. Holwerda, Gianni Tognoni, Jay N. Cohn
Journal: Circulation (2002)

Background— Brain natriuretic peptide (BNP) and norepinephrine (NE) are strongly related to severity of and are independent predictors of outcome in heart failure. The long-term effects of angiotensin receptor blockers on BNP and NE in heart failure patients are not known. Methods and Results— Both BNP and NE were measured in 4284 patients randomized to valsartan or placebo in the Valsartan Heart Failure Trial (Val-HeFT) at baseline and 4, 12, and 24 months after randomization. The effects of valsartan were tested by ANCOVA, controlling for baseline values and concomitant ACE inhibitors and/or β-blockers. BNP and NE concentrations were similar at baseline in the 2 groups and were decreased by valsartan starting at 4 months and up to 24 months. BNP increased over time in the placebo group. At the end point, least-squares mean (±SEM) BNP increased from baseline by 23±5 pg/mL in the placebo group (n=1979) but decreased by 21±5 pg/mL (n=1940) in the valsartan group ( P &lt;0.0001). NE increased by 41±6 pg/mL (n=1979) and 12±6 pg/mL (n=1941) for placebo and valsartan, respectively ( P =0.0003). Concomitant therapy with both ACE inhibitors and β-blockers significantly reduced the effect of valsartan on BNP but not on NE ( P for interaction=0.0223 and 0.2289, respectively). Conclusions— In Val-HeFT, the largest neurohormone study in patients with symptomatic chronic heart failure, BNP and NE rose over time in the placebo group. Valsartan caused sustained reduction in BNP and attenuated the increase in NE over the course of the study. These neurohormone effects of valsartan are consistent with the clinical benefits reported in Val-HeFT.
Functionally Competent Cardiac Stem Cells Can Be Isolated From Endomyocardial Biopsies of Patients With Advanced Cardiomyopathies
Authors: Domenico D'Amario, Claudia Fiorini, Patricia M. Campbell, Polina Goichberg, Fumihiro Sanada, Hanqiao Zheng, Toru Hosoda, Marcello Rota, John M. Connell, Robert P. Gallegos, Frederick G. Welt, Michael M. Givertz, Richard N. Mitchell, Annarosa Leri, Jan Kajstura, Marc A. Pfeffer, Piero Anversa
Journal: Circulation Research (2011)

Two categories of cardiac stem cells (CSCs) with predominantly myogenic (mCSC) and vasculogenic (vCSC) properties have been characterized in the human heart. However, it is unknown whether functionally competent CSCs of both classes are present in the myocardium of patients affected by end-stage cardiac failure, and whether these cells can be harvested from relatively small myocardial samples.To establish whether a clinically relevant number of mCSCs and vCSCs can be isolated and expanded from endomyocardial biopsies of patients undergoing cardiac transplantation or left ventricular assist device implantation.Endomyocardial biopsies were collected with a bioptome from the right side of the septum of explanted hearts or the apical LV core at the time of left ventricular assist device implantation. Two to 5 biopsies from each patient were enzymatically dissociated, and, after expansion, cells were sorted for c-kit (mCSCs) or c-kit and KDR (vCSCs) and characterized. mCSCs and vCSCs constituted 97% and 3% of the c-kit population, respectively. Population doubling time averaged 27 hours in mCSCs and vCSCs; 5×10(6) mCSCs and vCSCs were obtained in 28 and 41 days, respectively. Both CSC classes possessed significant growth reserve as documented by high telomerase activity and relatively long telomeres. mCSCs formed mostly cardiomyocytes, and vCSCs endothelial and smooth muscle cells.The growth properties of mCSCs and vCSCs isolated from endomyocardial biopsies from patients with advanced heart failure were comparable to those obtained previously from larger myocardial samples of patients undergoing elective cardiac surgery.
Phase I trial of combination chemotherapy with docetaxel, cisplatin and S-1 (TPS) in patients with locally advanced or recurrent/metastatic head and neck cancer
Authors: M. Tahara, K. Araki, S. Okano, N. Kiyota, N. Fuse, K. Minashi, T. Yoshino, T. Doi, S. Zenda, M. Kawashima, T. Ogino, R. Hayashi, H. Minami, A. Ohtsu
Journal: Annals of Oncology (2010)
Kinome-wide Functional Screen Identifies Role of PLK1 in Hormone-Independent, ER-Positive Breast Cancer
Authors: Neil E. Bhola, Valerie M. Jansen, Sangeeta Bafna, Jennifer M. Giltnane, Justin M. Balko, Mónica V. Estrada, Ingrid Meszoely, Ingrid Mayer, Vandana Abramson, Fei Ye, Melinda Sanders, Teresa C. Dugger, Eliezer V. Allen, Carlos L. Arteaga
Journal: Cancer Research (2014)

Estrogen receptor (ER) α-positive breast cancers initially respond to antiestrogens but eventually become estrogen independent and recur. ER(+) breast cancer cells resistant to long-term estrogen deprivation (LTED) exhibit hormone-independent ER transcriptional activity and growth. A kinome-wide siRNA screen using a library targeting 720 kinases identified Polo-like kinase 1 (PLK1) as one of the top genes whose downregulation resulted in inhibition of estrogen-independent ER transcriptional activity and growth of LTED cells. High PLK1 mRNA and protein correlated with a high Ki-67 score in primary ER(+) breast cancers after treatment with the aromatase inhibitor letrozole. RNAi-mediated knockdown of PLK1 inhibited ER expression, estrogen-independent growth, and ER transcription in MCF7 and HCC1428 LTED cells. Pharmacologic inhibition of PLK1 with volasertib, a small-molecule ATP-competitive PLK1 inhibitor, decreased LTED cell growth, ER transcriptional activity, and ER expression. Volasertib in combination with the ER antagonist, fulvestrant, decreased MCF7 xenograft growth in ovariectomized mice more potently than each drug alone. JUNB, a component of the AP-1 complex, was expressed 16-fold higher in MCF7/LTED compared with parental MCF7 cells. Furthermore, JUNB and BCL2L1 (which encodes antiapoptotic BCL-xL) mRNA levels were markedly reduced upon volasertib treatment in MCF7/LTED cells, while they were increased in parental MCF7 cells. Finally, JUNB knockdown decreased ER expression and transcriptional activity in MCF7/LTED cells, suggesting that PLK1 drives ER expression and estrogen-independent growth via JUNB. These data support a critical role of PLK1 in acquired hormone-independent growth of ER(+) human breast cancer and is therefore a promising target in tumors that have escaped estrogen deprivation therapy.
BCL-2 and Mutant NRAS Interact Physically and Functionally in a Mouse Model of Progressive Myelodysplasia
Authors: Nader Omidvar, Scott Kogan, Stephanie Beurlet, Carole le Pogam, Anne Janin, Robert West, Maria-Elena Noguera, Murielle Reboul, Annie Soulie, Christophe Leboeuf, Niclas Setterblad, Dean Felsher, Eric Lagasse, Azim Mohamedali, N. Shaun B. Thomas, Pierre Fenaux, Michaela Fontenay, Marika Pla, Ghulam J. Mufti, Irving Weissman, Christine Chomienne, Rose Ann Padua
Journal: Cancer Research (2007)

Abstract Myelodysplastic syndromes (MDS) are clonal stem cell hematologic disorders that evolve to acute myeloid leukemia (AML) and thus model multistep leukemogenesis. Activating RAS mutations and overexpression of BCL-2 are prognostic features of MDS/AML transformation. Using NRASD12 and BCL-2, we created two distinct models of MDS and AML, where human (h)BCL-2 is conditionally or constitutively expressed. Our novel transplantable in vivo models show that expression of hBCL-2 in a primitive compartment by mouse mammary tumor virus–long terminal repeat results in a disease resembling human MDS, whereas the myeloid MRP8 promoter induces a disease with characteristics of human AML. Expanded leukemic stem cell (Lin−/Sca-1+/c-Kit+) populations and hBCL-2 in the increased RAS-GTP complex within the expanded Sca-1+ compartment are described in both MDS/AML–like diseases. Furthermore, the oncogenic compartmentalizations provide the proapoptotic versus antiapoptotic mechanisms, by activating extracellular signal-regulated kinase and AKT signaling, in determination of the neoplastic phenotype. When hBCL-2 is switched off with doxycycline in the MDS mice, partial reversal of the phenotype was observed with persistence of bone marrow blasts and tissue infiltration as RAS recruits endogenous mouse (m)BCL-2 to remain active, thus demonstrating the role of the complex in the disease. This represents the first in vivo progression model of MDS/AML dependent on the formation of a BCL-2:RAS-GTP complex. The colocalization of BCL-2 and RAS in the bone marrow of MDS/AML patients offers targeting either oncogene as a therapeutic strategy. [Cancer Res 2007;67(24):11657–67]
Tolerance and immunity after sequential lung and bone marrow transplantation from an unrelated cadaveric donor
Authors: Paul Szabolcs, Rebecca H. Buckley, Robert Duane Davis, Jerelyn Moffet, Judith Voynow, Jeyaraj Antony, Xiaohua Chen, Gregory D. Sempowski, David W. Zaas
Journal: Journal of Allergy and Clinical Immunology (2014)
Patient experience of an airway clearance technique in a UK university hospital setting
Authors: Julie Young, Ruth Bennett, Anna Coad, Ari Manuel, Naj Rahman
Journal: European Respiratory Journal (2012)

Introduction  To gain insight into patient experiences using an airway clearance technique in a heterogeneous patient group with neuromuscular disease. The lung volume recruitment bag(LVR)utilises positive pressure to augment inspiratory volume and increase cough strength.   Method  Patients responded to a telephone questionnaire carried out by university members. Our study group was 8 patients aged 21-79 with either SMA, muscular dystrophy, motor neuron disease or spinal cord lesions. All patients had received a LVR bag within the past year and had been taught how to use it by a respiratory physiotherapist.   Results     Discussion  To our knowledge this is the first report of patient satisfaction using the innovative LVR bag. 6/8 patients were able to clear sputum more easily after using the LVR bag. 7/8 patients found the verbal instructions easy to follow and strongly agreed/agreed that the bag was easy to use. In 7/8 patients, the technique required the assistance of a carer. Our study shows the LVR bag is easy to use and aids patient sputum clearance. Therefore, this technique warrants further investigation in a larger population with a wider range of conditions.
Myoferlin Is a Key Regulator of EGFR Activity in Breast Cancer
Authors: Andrei Turtoi, Arnaud Blomme, Akeila Bellahcène, Christine Gilles, Vincent Hennequière, Paul Peixoto, Elettra Bianchi, Agnès Noel, Edwin De Pauw, Eric Lifrange, Philippe Delvenne, Vincent Castronovo
Journal: Cancer Research (2013)

Myoferlin is a member of the ferlin family of proteins that participate in plasma membrane fusion, repair, and endocytosis. While some reports have implicated myoferlin in cancer, the extent of its expression in and contributions to cancer are not well established. In this study, we show that myoferlin is overexpressed in human breast cancers and that it has a critical role in controlling degradation of the epidermal growth factor (EGF) receptor (EGFR) after its activation and internalization in breast cancer cells. Myoferlin depletion blocked EGF-induced cell migration and epithelial-to-mesenchymal transition. Both effects were induced as a result of impaired degradation of phosphorylated EGFR via dysfunctional plasma membrane caveolae and alteration of caveolin homo-oligomerization. In parallel, myoferlin depletion reduced tumor development in a chicken chorioallantoic membrane xenograft model of human breast cancer. Considering the therapeutic significance of EGFR targeting, our findings identify myoferlin as a novel candidate function to target for future drug development.