tbuckley/cabot-search huggingface dataset:
Pressure-Flow Relationships in the Coronary Circulation
Authors: Wadie M. Fam, Maurice McGregor
Journal: Circulation Research (1969)

This study was designed to define more accurately the respective influences of perfusion pressure and flow on coronary resistance. Resistance in a coronary branch, perfused at constant flow, was reduced immediately following temporary perfusion arrest. Large epicardial arteries did not appear to take part in this reaction. In the first 10 to 15 seconds after flow was restored, resistance for that flow was uninfluenced by the duration of the preceding perfusion arrest. That mechanism which caused coronary resistance to fall as a result of metabolic factors, such as reduced availability of oxygen, was thus maximally activated. By observing the relationship of coronary resistance to perfusion pressure at this time, it could be shown that resistance vessels and their surrounding structures showed little evidence of distensibility (resistance constant from 20 to 60 mm Hg). The difference between resistance at steady state and resistance at maximal vasodilatation defines the extent of vasomotion attributable at any flow rate to metabolic factors. Perfusion with venous blood caused a fall of resistance which was greater at any flow rate than could be accounted for by the differences in oxygen delivery rate.
Pro12Ala substitution in peroxisome proliferator-activated receptorγ2 is associated with low adiponectin concentrations in young Japanese men
Authors: Nobuki Takata, Takuya Awata, Kouichi Inukai, Masaki Watanabe, Tomoko Ohkubo, Susumu Kurihara, Munemichi Inaba, Shigehiro Katayama
Journal: Metabolism (2004)
-catenin tyrosine 654 phosphorylation increases Wnt signalling and intestinal tumorigenesis
Authors: W. van Veelen, N. H. Le, W. Helvensteijn, L. Blonden, M. Theeuwes, E. R. M. Bakker, P. F. Franken, L. van Gurp, F. Meijlink, M. A. van der Valk, E. J. Kuipers, R. Fodde, R. Smits
Journal: Gut (2011)

Objective Deregulation of the Wnt signalling pathway by mutations in the Apc or β-catenin genes underlies colorectal carcinogenesis. As a result, β-catenin stabilises, translocates to the nucleus, and activates gene transcription. Intestinal tumours show a heterogeneous pattern of nuclear β-catenin, with the highest levels observed at the invasion front. Activation of receptor tyrosine kinases in these tumour areas by growth factors expressed by surrounding stromal cells phosphorylate β-catenin at tyrosine residues, which is thought to increase β-catenin nuclear translocation and tumour invasiveness. This study investigates the relevance of β-catenin tyrosine phosphorylation for Wnt signalling and intestinal tumorigenesis in vivo. Design A conditional knock-in mouse model was generated into which the phospho-mimicking Y654E modification in the endogenous β-catenin gene was introduced. Results This study provided in vivo evidence that β-catenin(E654) is characterised by reduced affinity for cadherins, increased signalling and strongly increased phosphorylation at serine 675 by protein kinase A (PKA). In addition, homozygosity for the β-catenin(E654) targeted allele caused embryonic lethality, whereas heterozygosity predisposed to intestinal tumour development, and strongly enhanced Apc-driven intestinal tumour initiation associated with increased nuclear accumulation of βcatenin. Surprisingly, the expression of β-catenin(E654) did not affect histological grade or induce tumour invasiveness. Conclusions A thus far unknown mechanism was uncovered in which Y654 phosphorylation of β-catenin facilitates additional phosphorylation at serine 675 by PKA. In addition, in contrast to the current belief that β-catenin Y654 phosphorylation increases tumour progression to a more invasive phenotype, these results show that it rather increases tumour initiation by enhancing Wnt signalling.
Characterization of human memory CD4+ T-cell responses to the dog allergen Can f 4
Authors: Aino L Rönkä, Tuure T Kinnunen, Amélie Goudet, Marja A Rytkönen-Nissinen, Joni Sairanen, Anssi H T Kailaanmäki, Jukka T Randell, Bernard Maillère, Tuomas I Virtanen
Journal: Journal of Allergy and Clinical Immunology (2015)
Reflex effect of vasopressin after blockade of V1 receptors in the area postrema.
Authors: E M Hasser, V S Bishop
Journal: Circulation Research (1990)

This study investigated the effect of micropressure injection of the V1 arginine vasopressin (AVP) receptor antagonist into the area postrema on the ability of circulating AVP to augment baroreflex inhibition of renal sympathetic nerve activity (RSNA) in urethane-anesthetized rabbits. In addition, the effects of micropressure injections of AVP into the area postrema on RSNA, arterial pressure, heart rate, and baroreflex control of RSNA were evaluated. Injection of 100 ng (in a 10-nl volume) of AVP antagonist into the area postrema abolished the ability of AVP to enhance baroreflex inhibition of RSNA compared with phenylephrine (-8.84 +/- 0.89 before antagonist versus -4.83 +/- 0.44 %RSNA/mm Hg after antagonist). Normal baroreflex inhibition to phenylephrine (-3.95 +/- 0.26 versus -4.10 +/- 0.33 %RSNA/mm Hg) was unaltered. This dose of AVP antagonist given intravenously or into the adjacent medial nucleus tractus solitarius was without effect. Micropressure injection of AVP directly into the area postrema produced a dose-dependent decrease in RSNA without significant effects on arterial pressure or heart rate. Local injection of 4 +/- 0.6 ng (in a 4-nl volume) of AVP produced an average 27 +/- 3% decrease in resting RSNA. Continuous injection of AVP into the area postrema using short-duration, low-frequency pressure pulses significantly augmented the baroreflex inhibition of RSNA during phenylephrine infusion (during AVP injection, -7.12 +/- 1.60%RSNA/mm Hg; control, -3.38 +/- 0.55 %RSNA/mm Hg). These data support the hypothesis that circulating AVP acts at the area postrema to augment baroreflex inhibition of RSNA by a V1 receptor mechanism.
Increase in Circulating Endothelial Progenitor Cells by Statin Therapy in Patients With Stable Coronary Artery Disease
Authors: Mariuca Vasa, Stephan Fichtlscherer, Klaudia Adler, Alexandra Aicher, Hans Martin, Andreas M. Zeiher, Stefanie Dimmeler
Journal: Circulation (2001)

Background —Therapeutic neovascularization may constitute an important strategy to salvage tissue from critical ischemia. Circulating bone marrow–derived endothelial progenitor cells (EPCs) were shown to augment the neovascularization of ischemic tissue. In addition to lipid-lowering activity, hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) reportedly promote the neovascularization of ischemic tissue in normocholesterolemic animals. Methods and Results —Fifteen patients with angiographically documented stable coronary artery disease (CAD) were prospectively treated with 40 mg of atorvastatin per day for 4 weeks. Before and weekly after the initiation of statin therapy, EPCs were isolated from peripheral blood and counted. In addition, the number of hematopoietic precursor cells positive for CD34, CD133, and CD34/kinase insert domain receptor was analyzed. Statin treatment of patients with stable CAD was associated with an ≈1.5-fold increase in the number of circulating EPCs by 1 week after initiation of treatment; this was followed by sustained increased levels to ≈3-fold throughout the 4-week study period. Moreover, the number of CD34/kinase insert domain receptor–positive hematopoietic progenitor cells was significantly augmented after 4 weeks of therapy. Atorvastatin treatment increased the further functional activity of EPCs, as assessed by their migratory capacity. Conclusion —The results of the present study define a novel mechanism of action of statin treatment in patients with stable CAD: the augmentation of circulating EPCs with enhanced functional activity. Given the well-established role of EPCs of participating in repair after ischemic injury, stimulation of EPCs by statins may contribute to the clinical benefit of statin therapy in patients with CAD.
Myocardial Injection With GSK-3β–Overexpressing Bone Marrow–Derived Mesenchymal Stem Cells Attenuates Cardiac Dysfunction After Myocardial Infarction
Authors: Jaeyeaon Cho, Peiyong Zhai, Yasuhiro Maejima, Junichi Sadoshima
Journal: Circulation Research (2011)

Glycogen synthase kinase (GSK)-3β upregulates cardiac genes in bone marrow-derived mesenchymal stem cells (MSCs) in vitro. Ex vivo modification of signaling mechanisms in MSCs may improve the efficiency of cardiac cell-based therapy (CBT).To test the effect of GSK-3β on the efficiency of CBT with MSCs after myocardial infarction (MI).MSCs overexpressing either GSK-3β (GSK-3β-MSCs), LacZ (LacZ-MSCs), or saline was injected into the heart after coronary ligation. A significant improvement in the mortality and left ventricular (LV) function was observed at 12 weeks in GSK-3β-MSC-injected mice compared with in LacZ-MSC- or saline-injected mice. MI size and LV remodeling were reduced in GSK-3β-MSC-injected mice compared with in LacZ-MSC- or saline-injected ones. GSK-3β increased survival and increased cardiomyocyte differentiation of MSCs, as evidenced by activation of an Nkx2.5-LacZ reporter and upregulation of troponin T. Injection of GSK-3β-MSCs induced Ki67-positive myocytes and c-Kit-positive cells, suggesting that GSK-3β-MSCs upregulate cardiac progenitor cells. GSK-3β-MSCs also increased capillary density and upregulated paracrine factors, including vascular endothelial growth factor A (Vegfa). Injection of GSK-3β-MSCs in which Vegfa had been knocked down abolished the increase in survival and capillary density. However, the decrease in MI size and LV remodeling and the improvement of LV function were still observed in MI mice injected with GSK-3β-MSCs without Vegfa.GSK-3β significantly improves the efficiency of CBT with MSCs in the post-MI heart. GSK-3β not only increases survival of MSCs but also induces cardiomyocyte differentiation and angiogenesis through Vegfa-dependent and -independent mechanisms.
Genetic Ablation of Angiotensinogen in the Subfornical Organ of the Brain Prevents the Central Angiotensinergic Pressor Response
Authors: Puspha Sinnayah, Eric Lazartigues, Koji Sakai, Ram V. Sharma, Curt D. Sigmund, Robin L. Davisson
Journal: Circulation Research (2006)

The subfornical organ (SFO) of the brain has long been considered a critical integrating center for the cardiovascular actions of the renin-angiotensin system (RAS). Early reports of angiotensin II (Ang II) immunoreactivity in the SFO and its neural projections to downstream cardiovascular nuclei raised the possibility that Ang II is produced locally and functions as a putative neurotransmitter in these circuits. However, evidence of functionally significant de novo synthesis of Ang II in the SFO has been lacking. Here, implementing spatiotemporally restricted gene ablation by way of the Cre recombinase/loxP system, we provide the first direct evidence that the local RAS in the SFO has a critical role in blood pressure regulation. Using a transgenic mouse harboring an angiotensinogen (AGT) gene modified for Cre-mediated deletion (hAGT(flox)), in combination with gene transfer of an adenovirus encoding Cre targeted to the SFO, we show that deletion of the Ang II substrate in this brain region nearly abolishes the pressor and bradycardic effects of renin infused in the CNS. Immunohistochemical analyses verified intense and restricted expression of Cre in the SFO, which paralleled the decrease in AGT expression selectively in this site. Further physiological studies confirmed the integrity of central angiotensinergic and nonangiotensinergic cardiovascular response systems in the Cre-treated mice. In addition to establishing that AGT expression in the SFO and its local conversion to Ang II has a profound effect on blood pressure, this study provides proof-of-principle of the utility of this approach for dissecting the brain RAS and other complex systems in CNS cardiovascular circuits.
Targeted Cancer Therapy with a 2-Deoxyglucose–Based Adriamycin Complex
Authors: Jie Cao, Sisi Cui, Siwen Li, Changli Du, Junmei Tian, Shunan Wan, Zhiyu Qian, Yueqing Gu, Wei R. Chen, Guangji Wang
Journal: Cancer Research (2013)

Abstract Adriamycin (ADM) has been effective against many types of solid tumors in clinical applications. However, its use is limited because of systemic toxicities, primarily cardiotoxicity, and multidrug resistance. In this study, a new active receptor-mediated complex, ADM conjugated with 2-amino-2-deoxy-d-glucose and succinic acid (2DG–SUC–ADM), was designed to target tumor cells through glucose transporter 1 (GLUT1). MTT assay and confocal images showed that the complex had better inhibition rate to tumor cells and low toxicity to normal cells. Most importantly, the complex displayed a potential to reverse overcome multidrug resistance in cancer cells, with more complex transported into the nucleus of tumor cells. Our in vivo experiments also showed that this new complex could significantly decrease organ toxicity and enhance the antitumor efficacy compared with free ADM, indicating a promising drug of 2DG–SUC–ADM for targeted cancer therapy. Cancer Res; 73(4); 1362–73. ©2012 AACR.
The Role of Robot-assisted Radical Prostatectomy and Pelvic Lymph Node Dissection in the Management of High-risk Prostate Cancer: A Systematic Review
Authors: Bertram Yuh, Walter Artibani, Axel Heidenreich, Simon Kimm, Mani Menon, Giacomo Novara, Ashutosh Tewari, Karim Touijer, Timothy Wilson, Kevin C. Zorn, Scott E. Eggener
Journal: European Urology (2013)
Risk-Benefit Profiles of Women Using Tamoxifen for Chemoprevention
Authors: Hazel B. Nichols, Lisa A. DeRoo, Daniel R. Scharf, Dale P. Sandler
Journal: JNCI Journal of the National Cancer Institute (2014)

Background:Tamoxifen has been US Food and Drug Administration–approved for primary prevention of breast cancer since 1998 but has not been widely adopted, in part because of increased risk of serious side effects. Little is known about the risk-benefit profiles of women who use chemoprevention outside of a clinical trial. We examined characteristics associated with initiation and discontinuation of tamoxifen for primary prevention of breast cancer within a large cohort of women with a first-degree family history of breast cancer.
Lack of Resolution in the Animal Phylogeny: Closely Spaced Cladogeneses or Undetected Systematic Errors?
Authors: Denis Baurain, Henner Brinkmann, Hervé Philippe
Journal: Molecular Biology and Evolution (2006)

A recent phylogenomic study reported that the animal phylogeny was unresolved despite the use of 50 genes. This lack of resolution was interpreted as "a positive signature of closely spaced cladogenetic events." Here, we propose that this lack of resolution is rather due to the mutual cancellation of the phylogenetic signal (historical) and the nonphylogenetic signal (due to systematic errors) that results from inadequate taxon sampling and/or model of sequence evolution. Starting with a data set of comparable size, we use 3 different strategies to reduce the nonphylogenetic signal: 1) increasing the number of species; 2) replacing a fast-evolving species by a slowly evolving one; and 3) using a better model of sequence evolution. In all cases, the phylogenetic resolution is markedly improved, in agreement with our hypothesis that the originally reported lack of resolution was artifactual.
Association of alpha1-antichymotrypsin deficiency with milder lung disease in patients with cystic fibrosis
Authors: R Mahadeva
Journal: Thorax (2001)

<h3>BACKGROUND</h3> Cystic fibrosis (CF) is characterised by an excess of free proteinases that destroy lung tissue. Despite this, previous studies have shown that patients with CF with a mild deficiency variant of the proteinase inhibitor α<sub>1</sub>-antitrypsin have less, rather than more, severe pulmonary disease. Alpha<sub>1</sub>-antichymotrypsin is another important serine proteinase inhibitor that protects the lung against proteolytic attack, and point mutations in the α<sub>1</sub>-antichymotrypsin gene that result in plasma deficiency are associated with chronic obstructive pulmonary disease. <h3>METHODS</h3> The effect of α<sub>1</sub>-antichymotrypsin deficiency and the –15 α<sub>1</sub>-antichymotrypsin signal peptide genotype on lung function was assessed in patients with CF. <h3>RESULTS</h3> One hundred and fifty seven patients with CF were screened and 10 were identified with a plasma deficiency of α<sub>1</sub>-antichymotrypsin (plasma concentration &lt;0.2 g/l). In a multivariate analysis these individuals had significantly less severe lung disease than those who had normal or raised levels of α<sub>1</sub>-antichymotrypsin: forced expiratory volume in one second (FEV<sub>1</sub>) 69.9% predicted versus 53.2% predicted (p=0.04) and chest radiographic score of 7.2 versus 9.7 (p=0.03) for those with and without α<sub>1</sub>-antichymotrypsin deficiency, respectively. The –15 signal peptide genotype did not affect plasma levels, but the –15 Ala/Ala signal peptide genotype was over-represented in individuals with CF compared with healthy blood donor controls. <h3>CONCLUSION</h3> These data indicate that deficiency of α<sub>1</sub>-antichymotrypsin is associated with less severe pulmonary disease in patients with CF, and support our previous observations that mild genetic deficiency of a proteinase inhibitor is associated with an improved outcome.
Innovative Dietary Sources of N-3 Fatty Acids
Authors: Jay Whelan, Cheryl Rust
Journal: Annual Review of Nutrition (2006)

It is now established that dietary n-3 polyunsaturated fatty acids (PUFAs) are involved in health promotion and disease prevention, particularly those traditionally derived from marine sources (e.g., eicosapentaenoic acid and docosahexaenoic acid). A number of organizations have made specific recommendations for the general population to increase their intakes of these nutrients. In response to and along with these recommendations, n-3 PUFAs are being incorporated into nontraditional food sources because of advances in the technology to safely enrich/fortify our food supply. Fatty acid compositions of traditional oils (e.g., canola and soybean) are being genetically modified to deliver more highly concentrated sources of n-3 PUFA. The advent of algal sources of docosahexaenoic acid provides one of the few terrestrial sources of this fatty acid in a concentrated form. All of this is possible because of newer technologies (microencapsulation) and improved processing techniques that ensure stability and preserve the integrity of these unstable fatty acids.
European Treatment and Outcome Study (EUTOS) Score for Chronic Myeloid Leukemia Still Requires More Confirmation
Authors: David Marin, Amr R. Ibrahim, John M. Goldman
Journal: Journal of Clinical Oncology (2011)

TO THEEDITOR: In 1984, Sokal et al 1 developed a scoring system to predict the outcome of patients with chronic myeloid leukemia (CML). The scoring system rapidly gained popularity and has remained until now the most widely accepted method for assessing prognosisforpatientswithCML.AlthoughtheSokalscorewasdeveloped for patients with nonblastic disease who were treated with hydroxyureaorbusulfan,italsoprovedusefulforpredictingthesurvival of patients treated with interferon 2 and can predict the outcome for patients treated with imatinib. 3,4 Interestingly, it also predicts the outcome for patients who receive imatinib after experiencing treatment failure with interferon 5 and for patients who receive secondgeneration tyrosine kinase inhibitors after experiencing treatment failurewithimatinib. 6 TheconsistentvalueoftheSokalscoringsystem
Masked Uncontrolled Hypertension in CKD
Authors: Rajiv Agarwal, Maria K. Pappas, Arjun D. Sinha
Journal: Journal of the American Society of Nephrology (2015)

Masked uncontrolled hypertension (MUCH) is diagnosed in patients treated for hypertension who are normotensive in the clinic but hypertensive outside. In this study of 333 veterans with CKD, we prospectively evaluated the prevalence of MUCH as determined by ambulatory BP monitoring using three definitions of hypertension (daytime hypertension ≥135/85 mmHg; either nighttime hypertension ≥120/70 mmHg or daytime hypertension; and 24-hour hypertension ≥130/80 mmHg) or by home BP monitoring (hypertension ≥135/85 mmHg). The prevalence of MUCH was 26.7% by daytime ambulatory BP, 32.8% by 24-hour ambulatory BP, 56.1% by daytime or night-time ambulatory BP, and 50.8% by home BP. To assess the reproducibility of the diagnosis, we repeated these measurements after 4 weeks. Agreement in MUCH diagnosis by ambulatory BP was 75-78% (κ coefficient for agreement, 0.44-0.51), depending on the definition used. In contrast, home BP showed an agreement of only 63% and a κ coefficient of 0.25. Prevalence of MUCH increased with increasing clinic systolic BP: 2% in the 90-110 mmHg group, 17% in the 110-119 mmHg group, 34% in the 120-129 mmHg group, and 66% in the 130-139 mmHg group. Clinic BP was a good determinant of MUCH (receiver operating characteristic area under the curve 0.82; 95% confidence interval 0.76-0.87). In diagnosing MUCH, home BP was not different from clinic BP. In conclusion, among people with CKD, MUCH is common and reproducible, and should be suspected when clinic BP is in the prehypertensive range. Confirmation of MUCH diagnosis should rely on ambulatory BP monitoring.
Temporally Controlled Onset of Dilated Cardiomyopathy Through Disruption of the <i>SRF</i> Gene in Adult Heart
Authors: Ara Parlakian, Claude Charvet, Brigitte Escoubet, Mathias Mericskay, Jeffery D. Molkentin, Guillaume Gary-Bobo, Leon J. De Windt, Marie-Aline Ludosky, Denise Paulin, Dominique Daegelen, David Tuil, Zhenlin Li
Journal: Circulation (2005)

Serum response factor (SRF) is a cardiac transcription factor involved in cell growth and differentiation. We have shown, using the Cre/loxP system, that cardiac-specific disruption of SRF gene in the embryonic heart results in lethal cardiac defects. The role of SRF in adult heart is unknown.We disrupted SRF in the adult heart using a heart-specific tamoxifen-inducible Cre recombinase. This disruption led to impaired left ventricular function with reduced contractility, subsequently progressing to dilated cardiomyopathy, as demonstrated by serial echocardiography, including tissue Doppler imaging. The cytoarchitecture of cardiomyocytes was altered in the intercalated disks. All mutant mice died from heart failure 10 weeks after treatment. These functional and structural defects were preceded by early alterations in the cardiac gene expression program: major decreases in mRNA levels for cardiac alpha-actin, muscle creatine kinase, and calcium-handling genes.SRF is crucial for adult cardiac function and integrity. We suggest that the rapid progression to heart failure in SRF mutant mice results primarily from decreased expression of proteins involved in force generation and transmission, low levels of polymerized actin, and changes in cytoarchitecture, without hypertrophic compensation. These cardiac-specific SRF-deficient mice have the morphological and clinical features of acquired dilated cardiomyopathy in humans and may therefore be used as an inducible model of this disorder.