tbuckley/cabot-search huggingface dataset:
The function of heme-regulated eIF2α kinase in murine iron homeostasis and macrophage maturation
Authors: Sijin Liu, Rajasekhar N.V.S. Suragani, Fudi Wang, Anping Han, Wanting Zhao, Nancy C. Andrews, Jane-Jane Chen
Journal: Journal of Clinical Investigation (2007)

Heme-regulated eIF2alpha kinase (HRI) plays an essential protective role in anemias of iron deficiency, erythroid protoporphyria, and beta-thalassemia. In this study, we report that HRI protein is present in murine macrophages, albeit at a lower level than in erythroid precursors. Hri-/- mice exhibited impaired macrophage maturation and a weaker antiinflammatory response with reduced cytokine production upon LPS challenge. The level of production of hepcidin, an important player in the pathogenesis of the anemia of inflammation, was significantly decreased in Hri-/- mice, accompanied by decreased splenic macrophage iron content and increased serum iron content. Hepcidin expression was also significantly lower, with a concomitant increase in serum iron in Hri-/- mice upon LPS treatment. We also demonstrated an impairment of erythrophagocytosis by Hri-/- macrophages both in vitro and in vivo under chronic hemolytic anemia, providing evidence for the role of HRI in recycling iron from senescent red blood cells. This work demonstrates that HRI deficiency attenuates hepcidin expression and iron homeostasis in mice, indicating a potential role for HRI in the anemia of inflammation.
Controversial Role of Bevacizumab in the Development of Venous Thromboembolic Events
Authors: Sanjaykumar Hapani, Shenhong Wu
Journal: Journal of Clinical Oncology (2011)

read the article by Hurwitz et al 1 on the venous thromboembolic events (VTEs) with chemotherapy plus bevacizumab in patients with cancer that was based on a meta-analysis of individual patient data with great interest.We would like to make three comments that are relevant to the conclusion of the study, which is not consistent with our previous analysis. 2irst, the overall conclusion of bevacizumab's effect on VTEs depends on the studies included for the meta-analysis.This study included 10 randomized controlled clinical trials, which may be a small fraction of total bevacizumab trials.The article did not mention how many studies the authors had screened before the final selection of these trials.The difference in the number of included trials between this study and our previous meta-analysis 2 is substantial; although the two meta-analyses shared the same eight studies, they differed in a total of nine trials; the current study had added two new studies by Miles et al 3 and Van Cutsem et al 4 with a calculated summary risk ratio of 0.82 (95% CI, 0.60 to 1.11) and did not have seven other trials with asummaryrelativeriskof1.27(95%CI,0.94to1.73)whichwereincluded in our study. 2Thus, the determination of overall RR by this study will be most likely underestimated by the addition and exclusion of these studies.Second, the exposure-adjusted incidence as rate per 100 patientyears according to progression-free survival to estimate the risk may introduce a bias of underestimation.This is based on the assumption that these VTEs occurred evenly over time and were directly proportional to the duration.As shown in the Kaplan-Meier analysis in Figure 3 of the article, 1 the events tend to occur early after the drug therapy.In addition, as reported in the article, the median time to VTE was 2.2 months for the bevacizumab group and 1.7 months for the control group, which suggests the events did not occur equally over the exposure time.Third, retrospective studies tend to substantially underestimate the incidence of VTEs as a result of insufficient and irregular detection.To fully and accurately understand the effect of bevacizumab on the risk of VTEs, it would be ideal to perform a randomized controlled trial with a primary end point of VTEs measured prospectively and regularly.
An Electromagnetic Catheter-Flowmeter
Authors: ALEXANDER KOLIN, JAMES D. ARCHER, GORDON ROSS
Journal: Circulation Research (1967)

An electromagnetic flowmeter incorporated into a catheter is described. The catheter is introduced into the aorta via the femoral artery. The flow sensor is located some distance below the catheter tip and is sensitive to flow at right angles to the catheter. A crater-like elevation at one end of the transducer lumen permits funnel-like connection of the transducer to the ostium of an aortic branch. The transducer thus measures the blood flow through a selected branch of the aorta. It is pressed against the branch artery by arching the catheter by means of a pull-wire. A reliable and readily reproducible zero-flow baseline is obtained by slightly withdrawing the lumen of the transducer from the branch ostium, thus closing the lumen by the aortic wall. Records of phasic blood flow in the left renal and superior mesenteric arteries of a dog are presented. The calibration was accomplished by comparison with a calibrated noncannulating electromagnetic flow transducer. Reliable calibration can also be performed in vitro.
The physiologic effects of digoxin under steady-state drug conditions in newborn and adult sheep.
Authors: W Berman, J Musselman, R Shortencarrier
Journal: Circulation (1980)

The physiologic response to the chronic administration of digoxin was studied in 12 adult and 13 newborn sheep. Vascular pressures, cardiac output, isovolumic contraction phase indexes and systolic time intervals were measured before and after 2 weeks of digoxin therapy. Physiologic measurements were correlated with drug levels in plasma and myocardium. Resting myocardial function in newborns exceeded that in ewes. In ewes, the heart rate decreased from 98 to 74 beats/min, the preejection period (PEP) decreased from 76 to 57 msec, the ratio of PEP to left ventricular ejection time (LVET) decreased from 0.323 to 0.223 and dP/dt max increased from 2415 to 3460 mm Hg . sec-1 as plasma concentrations of digoxin increased to a mean of 1.8 ng/ml. Although the final steady-state plasma concentration of digoxin in newborn lambs averaged 1.7 ng/ml, cardiac output, PEP, PEP/LVET and dP/dt max did not change significantly from baseline values. These studies suggest that developmental differences in the physiologic response to digoxin are due either to a limited capacity for improvement in myocardial contractility shortly after birth or to an age-related difference in the effect of digoxin on myocardial tissue.
Fasudil reduces monocrotaline-induced pulmonary arterial hypertension: comparison with bosentan and sildenafil
Authors: K.T.B. Mouchaers, I. Schalij, M.A. de Boer, P.E. Postmus, V.W.M. van Hinsbergh, G.P. van Nieuw Amerongen, A. Vonk Noordegraaf, W.J. van der Laarse
Journal: European Respiratory Journal (2010)

Pulmonary arterial hypertension (PAH) still cannot be cured, warranting the search for novel treatments. Fasudil (a Rho kinase inhibitor) was compared with bosentan (an endothelin receptor blocker) and sildenafil (a phosphodiesterase 5 inhibitor), with emphasis on right ventricular (RV) function, in a reversal rat model of monocrotaline (MCT)-induced PAH. In addition, the effects of combining bosentan or sildenafil with fasudil were studied. MCT (40 mg·kg body weight −1 ) induced clear PAH in male Wistar rats (n = 9). After 28 days, echocardiography, RV catheterisation and histochemistry showed that cardiac frequency, stroke volume and RV contractility had deteriorated, accompanied by RV dilatation and hypertrophy, and marked pulmonary arterial wall thickening. Mean pulmonary arterial pressure and pulmonary vascular resistance increased significantly compared to healthy rats (n = 9). After 14 days, MCT-treated rats received a 14-day oral treatment with bosentan, sildenafil, fasudil or a combination of fasudil with either bosentan or sildenafil (all n = 9). All treatments preserved cardiac frequency, stroke volume and RV contractility, and reduced pulmonary vascular resistance and RV dilatation. Fasudil lowered RV systolic pressure and mean pulmonary arterial pressure significantly, by reducing pulmonary arterial remodelling, which reduced RV hypertrophy. Combining bosentan or sildenafil with fasudil had no synergistic effect. Fasudil significantly improved PAH, to a greater degree than did bosentan and sildenafil.
Purine-Rich Box-1–Mediated Reduced Expression of CD20 Alters Rituximab-Induced Lysis of Chronic Lymphocytic Leukemia B Cells
Authors: Amani Mankaï, Anne Bordron, Yves Renaudineau, Christine Martins-Carvalho, Shinichiro Takahashi, Ibtissem Ghedira, Christian Berthou, Pierre Youinou
Journal: Cancer Research (2008)

Abstract The anti-CD20 monoclonal antibody rituximab has been less successful in treating chronic lymphocytic leukemia (CLL) than lymphoma, possibly due to the lower density of CD20 on B lymphocytes from CLL patients than on those from lymphoma patients. This lowering may result from insufficiency of one of the transcription factors of cd20. Of these, purine-rich box-1 (PU.1) is poorly expressed in CLL. To estimate its weight in CD20 expression, pu.1 cDNA was transfected into CLL B cells and shown to raise the membrane expression of CD20 and to improve the rituximab-induced lysis of transfected cells. Granulocyte macrophage colony-stimulating factor and all-trans-retinoic acids were not involved in the defective expression of PU.1 or the excessive methylation of the pu.1 gene, because 6 of 14 CLL samples tested were normally methylated. This was confirmed by the failure of DNA methyltransferase inhibitors to restore pu.1 transcription in hypermethylated CLL, and, in fact, the expression of PU.1 was down-regulated by excessive expression of the FMS proto-oncogene–like tyrosine kinase 3 (Flt3) receptor. This abnormality is consistent with our finding of elevated levels of Flt3 ligand (FL) in 20 of 23 CLL sera tested. We propose that FL-dependent increased Flt3 signaling prevents the expression of PU.1, which down-regulates that of CD20, and accounts for resistance of leukemic B cells to rituximab-induced lysis. [Cancer Res 2008;68(18):7512–9]
Low PIP4K2B Expression in Human Breast Tumors Correlates with Reduced Patient Survival: A Role for PIP4K2B in the Regulation of E-Cadherin Expression
Authors: Willem-Jan Keune, Andrew H. Sims, David R. Jones, Yvette Bultsma, James T. Lynch, Karin Jirström, Goran Landberg, Nullin Divecha
Journal: Cancer Research (2013)

Abstract Phosphatidylinositol-5-phosphate (PtdIns5P) 4-kinase β (PIP4K2B) directly regulates the levels of two important phosphoinositide second messengers, PtdIns5P and phosphatidylinositol-(4,5)-bisphosphate [PtdIns(4,5)P2]. PIP4K2B has been linked to the regulation of gene transcription, to TP53 and AKT activation, and to the regulation of cellular reactive oxygen accumulation. However, its role in human tumor development and on patient survival is not known. Here, we have interrogated the expression of PIP4K2B in a cohort (489) of patients with breast tumor using immunohistochemical staining and by a meta-analysis of gene expression profiles from 2,999 breast tumors, both with associated clinical outcome data. Low PIP4K2B expression was associated with increased tumor size, high Nottingham histological grade, Ki67 expression, and distant metastasis, whereas high PIP4K2B expression strongly associated with ERBB2 expression. Kaplan–Meier curves showed that both high and low PIP4K2B expression correlated with poorer patient survival compared with intermediate expression. In normal (MCF10A) and tumor (MCF7) breast epithelial cell lines, mimicking low PIP4K2B expression, using short hairpin RNA interference-mediated knockdown, led to a decrease in the transcription and expression of the tumor suppressor protein E-cadherin (CDH1). In MCF10A cells, knockdown of PIP4K2B enhanced TGF-β–induced epithelial to mesenchymal transition (EMT), a process required during the development of metastasis. Analysis of gene expression datasets confirmed the association between low PIP4K2B and low CDH1expression. Decreased CDH1 expression and enhancement of TGF-β–induced EMT by reduced PIP4K2B expression might, in part, explain the association between low PIP4K2B expression and poor patient survival. Cancer Res; 73(23); 6913–25. ©2013 AACR.
Transforming growth factor- gene polymorphisms in different phenotypes of sarcoidosis
Authors: S. Pabst, T. Fränken, J. Schönau, S. Stier, G. Nickenig, R. Meyer, D. Skowasch, C. Grohé
Journal: European Respiratory Journal (2010)

The aetiology of sarcoidosis is unclear. Single nucleotide polymorphisms (SNPs) in transforming growth factor (TGF)-β2 and -β3 have been reported to be associated with the development of lung fibrosis in patients with sarcoidosis. SNPs in TGF-β2 (rs1891467) and TGF-β3 (rs3917200) were investigated in 296 patients with sarcoidosis (acute/self remitting, n = 70 (including 62 patients with Löfgren's syndrome); chronic, n = 168; acute/chronic, n = 58) by real-time PCR. 32 patients showed radiological signs of lung fibrosis. The genotype frequencies were compared among the sarcoidosis groups as well as to 377 healthy controls. We found a significant association with the G-allele in rs1891467 in TGF-β2 and an acute/self remitting course of sarcoidosis compared to a chronic course (p = 0.001). The results were even more evident for patients with Löfgren's syndrome (p&lt;0.001). Moreover, we could demonstrate a borderline significance between TGF-β3 (rs3917200) and lung fibrosis (p = 0.050). Carriers of the G-allele in rs1891467 might be protected from developing a chronic course. Moreover, there is evidence that rs3917200 is involved in the development of lung fibrosis in sarcoidosis. This study is the first in sarcoidosis patients to suggest a genetic implication of TGF-β2 as a protective factor in the course of sarcoidosis.
Ancient papillomavirus-host co-speciation in Felidae
Authors: Annabel Rector, Philippe Lemey, Ruth Tachezy, Sara Mostmans, Shin-Je Ghim, Koenraad Van Doorslaer, Melody Roelke, Mitchell Bush, Richard J Montali, Janis Joslin, Robert D Burk, Alfred B Jenson, John P Sundberg, Beth Shapiro, Marc Van Ranst
Journal: Genome biology (2007)

Abstract Background Estimating evolutionary rates for slowly evolving viruses such as papillomaviruses (PVs) is not possible using fossil calibrations directly or sequences sampled over a time-scale of decades. An ability to correlate their divergence with a host species, however, can provide a means to estimate evolutionary rates for these viruses accurately. To determine whether such an approach is feasible, we sequenced complete feline PV genomes, previously available only for the domestic cat ( Felis domesticus , FdPV1), from four additional, globally distributed feline species: Lynx rufus PV type 1, Puma concolor PV type 1, Panthera leo persica PV type 1, and Uncia uncia PV type 1. Results The feline PVs all belong to the Lambdapapillomavirus genus, and contain an unusual second noncoding region between the early and late protein region, which is only present in members of this genus. Our maximum likelihood and Bayesian phylogenetic analyses demonstrate that the evolutionary relationships between feline PVs perfectly mirror those of their feline hosts, despite a complex and dynamic phylogeographic history. By applying host species divergence times, we provide the first precise estimates for the rate of evolution for each PV gene, with an overall evolutionary rate of 1.95 × 10 -8 (95% confidence interval 1.32 × 10 -8 to 2.47 × 10 -8 ) nucleotide substitutions per site per year for the viral coding genome. Conclusion Our work provides evidence for long-term virus-host co-speciation of feline PVs, indicating that viral diversity in slowly evolving viruses can be used to investigate host species evolution. These findings, however, should not be extrapolated to other viral lineages without prior confirmation of virus-host co-divergence.
The NER proteins are differentially expressed in ever smokers and in never smokers with lung adenocarcinoma
Authors: D. Planchard, J. Domont, E. Taranchon, I. Monnet, J. Tredaniel, R. Caliandro, P. Validire, B. Besse, J.-C. Soria, P. Fouret
Journal: Annals of Oncology (2009)
Abnormal Lung Function in Healthy Preterm Infants
Authors: OLA HJALMARSON, KENNETH SANDBERG
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

The aim of this study was to assess the consequences of preterm birth for the functional development of the lungs. We studied 32 healthy preterm infants (gestational age 25 to 33 wk at birth) and 53 healthy full-term infants (37 to 42 wk) at the same mean postmenstrual age of 40 wk with a multibreath nitrogen washout technique to assess functional residual capacity (FRC), gas mixing efficiency, and dead space and with the single-breath occlusion technique to calculate compliance and resistance of the respiratory system. Twenty of the preterm infants were also assessed with the same methods at 34.2 (32 to 37) wk. At the same postmenstrual age the preterm infants had lower FRC/kg body weight, lower specific compliance, impaired gas mixing efficiency, and higher total and dead space ventilation/kg than the full-term infants. Specific compliance and specific conductance decreased but gas mixing efficiency increased from 34 to 40 wk. We conclude that premature exposure to extrauterine conditions changes lung function. Preterm infants showed signs of dysfunction of the terminal respiratory units and higher elastic recoil than infants who spent the corresponding time for development in utero. It is suggested that preterm birth per se affects alveolarization and formation of elastic tissue in the lungs.
Collagen biosynthesis in normal and abnormal human heart valves
Authors: A. M HENNEY, D J. PARKER, M. J DAVIES
Journal: Cardiovascular Research (1982)

Absolute rates of collagen and non-collagen protein synthesis were measured in organ cultures of normal, rheumatic and floppy heart valves. The incorporation of 14C-proline into the cultures was measured and standardised according to the specific activity of the isotope in the tissue and the amount of DNA present. It was observed that the mean rate of collagen synthesis in floppy and rheumatic valves was significantly higher than normal, but that there was no difference in the rates of non-collagen protein synthesis. This stimulated synthetic activity in the abnormal valves was coupled with elevated collagen and total protein content of the tissue. The proportion of total protein synthesis that was devoted to the production of collagen was also significantly higher in the pathological tissues.
AN ALUMINUM MARKER FOR THE DIFFERENTIATION AND SEPARATION OF VIRULENT AND ATTENUATED POLIOVIRUSES
Authors: Craig Wallis, Joseph L. Melnick, George D. Ferry, Ira L. Wimberly
Journal: The Journal of Experimental Medicine (1962)

A new character, the A marker, for polioviruses is described. In the presence of Al(+++) (1 to 100 mM) attenuated, but not virulent, strains of type 1 and type 2 polioviruses are stabilized so that they resist thermal inactivation at 50 degrees C. Differences between the attenuated and virulent type 3 strains studied were of the opposite character and less marked. By the use of optimal concentrations of Al(+++) (12 mM for type 1 and 1 mM for type 2) attenuated strains can be separated from mixtures containing virulent type 1 or 2 strains. The A marker was found to be correlated with the d but not the rct/40 or T marker. The A marker has been used for following genetic changes of vaccine strains after their multiplication in man.
Neural Mechanisms of Paroxysmal Atrial Fibrillation and Paroxysmal Atrial Tachycardia in Ambulatory Canines
Authors: Alex Y. Tan, Shengmei Zhou, Masahiro Ogawa, Juan Song, Matthew Chu, Hongmei Li, Michael C. Fishbein, Shien-Fong Lin, Lan S. Chen, Peng-Sheng Chen
Journal: Circulation (2008)

The relationship between autonomic activation and the mechanisms of paroxysmal atrial fibrillation remains unclear.We implanted a pacemaker and a radio transmitter in 7 dogs (group 1). After baseline recording, we paced the left atrium at 20 Hz for 1 week and then monitored left stellate ganglion nerve activity, left vagal nerve activity, and left atrial electrogram without pacing for 24 hours. This protocol repeated itself until sustained atrial fibrillation (>48 hours) was induced in 3+/-1 weeks. In another 6 dogs (group 2), we cryoablated left and right stellate ganglia and the cardiac branch of the left vagal nerve during the first surgery and then repeated the same pacing protocol until sustained atrial fibrillation was induced in 7+/-4 weeks (P=0.01). There were 4+/-2 episodes of paroxysmal atrial fibrillation per day and 10+/-3 episodes of paroxysmal atrial tachycardia per day in group 1. Simultaneous sympathovagal discharges were observed to immediately precede the onset of atrial arrhythmias in 73% of episodes. In comparison, group 2 dogs had no paroxysmal atrial fibrillation (P=0.046) or paroxysmal atrial tachycardia (P<0.001) episodes. Nerve sprouting, sympathetic hyperinnervation, and a massive elevation of transcardiac norepinephrine levels occurred in both groups.Intermittent rapid left atrial pacing results in sympathetic hyperinnervation, paroxysmal atrial fibrillation, and paroxysmal atrial tachycardia. Simultaneous sympathovagal discharges are common triggers of these arrhythmias. Cryoablation of extrinsic sympathovagal nerves eliminated paroxysmal atrial fibrillation and paroxysmal atrial tachycardia, which suggests that simultaneous sympathovagal discharges and these arrhythmias are causally related. Because cryoablation only delayed but did not prevent sustained atrial fibrillation, autonomic nerve activity is not the only factor that determines atrial fibrillation maintenance.
Defects in sarcolemmal Ca2+ transport in hearts due to induction of calcium paradox.
Authors: N Makino, V Panagia, M P Gupta, N S Dhalla
Journal: Circulation Research (1988)

Na+-Ca2+ exchange and Ca2+-pump activities were studied in sarcolemmal vesicles isolated from rat hearts subjected to "calcium paradox" on perfusion with Ca2+-free medium followed by reperfusion with medium containing 1.25 mM Ca2+. Perfusion of hearts with Ca2+-free medium for 5 minutes did not affect the Na+-dependent Ca2+ uptake, ATP-dependent Ca2+ uptake, or Ca2+-stimulated ATPase activities in sarcolemma. Reperfusion of the Ca2+-deprived hearts with medium containing Ca2+ for 1-2 minutes increased Na+-dependent Ca2+ uptake, whereas reperfusion for 5-10 minutes decreased Na+-dependent Ca2+ uptake in sarcolemmal vesicles. Both ATP-dependent Ca2+ uptake and Ca2+-stimulated ATPase activities in sarcolemma were depressed on reperfusion of Ca2+-deprived hearts for 2-10 minutes. Reperfusion of Ca2+-deprived hearts for 5 minutes, which failed to generate contractile force, resulted in contracture without any recovery of the contractile force development. These changes in sarcolemmal Ca2+ transport and contractile function were prevented when hearts were perfused with Ca2+-free medium either in the presence of low sodium (35 mM) or at a low temperature (21 degrees C) before starting the reperfusion. No alterations in the purity of the preparation or permeability of sarcolemmal vesicles with respect to Na+ or Ca2+ were detected in hearts perfused with Ca2+-free medium or on reperfusion with medium containing calcium. The results indicate abnormalities in sarcolemmal Na+-Ca2+ exchange and Ca2+-pump mechanisms on reperfusion of Ca2+-deprived hearts with medium containing Ca2+, and such changes may partly account for the occurrence of intracellular Ca2+ overload during the development of calcium paradox.