tbuckley/cabot-search huggingface dataset:
Upregulation of Alveolar Epithelial Active Na <sup>+</sup> Transport Is Dependent on β <sub>2</sub> -Adrenergic Receptor Signaling
Authors: Gökhan M. Mutlu, Vidas Dumasius, James Burhop, Pamela J. McShane, Fan Jing Meng, Lynn Welch, Andrew Dumasius, Nima Mohebahmadi, Gloria Thakuria, Karen Hardiman, Sadis Matalon, Steven Hollenberg, Phillip Factor
Journal: Circulation Research (2004)

Alveolar epithelial beta-adrenergic receptor (betaAR) activation accelerates active Na+ transport in lung epithelial cells in vitro and speeds alveolar edema resolution in human lung tissue and normal and injured animal lungs. Whether these receptors are essential for alveolar fluid clearance (AFC) or if other mechanisms are sufficient to regulate active transport is unknown. In this study, we report that mice with no beta1- or beta2-adrenergic receptors (beta1AR-/-/beta2AR-/-) have reduced distal lung Na,K-ATPase function and diminished basal and amiloride-sensitive AFC. Total lung water content in these animals was not different from wild-type controls, suggesting that betaAR signaling may not be required for alveolar fluid homeostasis in uninjured lungs. Comparison of isoproterenol-sensitive AFC in mice with beta1- but not beta2-adrenergic receptors to beta1AR-/-/beta2AR-/- mice indicates that the beta2AR mediates the bulk of beta-adrenergic-sensitive alveolar active Na+ transport. To test the necessity of betaAR signaling in acute lung injury, beta1AR-/-/beta2AR-/-, beta1AR+/+/beta2AR-/-, and beta1AR+/+/beta2AR+/+ mice were exposed to 100% oxygen for up to 204 hours. beta1AR-/-/beta2AR-/- and beta1AR+/+/beta2AR-/- mice had more lung water and worse survival from this form of acute lung injury than wild-type controls. Adenoviral-mediated rescue of beta2-adrenergic receptor (beta2AR) function into the alveolar epithelium of beta1AR-/-/beta2AR-/- and beta1AR+/+/beta2AR-/- mice normalized distal lung beta2AR function, alveolar epithelial active Na+ transport, and survival from hyperoxia. These findings indicate that betaAR signaling may not be necessary for basal AFC, and that beta2AR is essential for the adaptive physiological response needed to clear excess fluid from the alveolar airspace of normal and injured lungs.
The prognostic value of hepatic venous pressure gradient in patients with cirrhosis is highly dependent on the accuracy of the technique
Authors: Gilberto Silva‐Junior, Anna Baiges, Fanny Turon, Ferran Torres, Virginia Hernández‐Gea, Jaime Bosch, Juan Carlos García‐Pagán
Journal: Hepatology (2015)

Hepatic venous pressure gradient (HVPG), the difference between wedged (WHVP) and free hepatic vein pressure (FHVP), predicts survival in patients with cirrhosis. It has been suggested for the use of inferior vena cava (IVC) value instead of FHVP to calculate HVPG when the difference between proximal FHVP (obtained at 2 cm from the hepatic vein outlet) and IVC (measured at the level of the hepatic ostium) is >2 mm Hg. However, there are no data supporting this recommendation. The main aim of the study was to establish which gradient, WHVP-FHVP (HVPG-Free) or WHVP-IVC (HVPG-IVC), better correlates with orthotopic liver transplantation (OLT)-free survival. This work was a retrospective evaluation of hepatic hemodynamic studies of 380 consecutive patients with cirrhosis performed from January 2006 to December 2012 with follow-up until December 2013. Patients had a mean age of 56±10 years and 64.7% were men. Mean Child-Pugh was 7±2. HVPG-Free (16±5 mm Hg) was significantly lower than HVPG-IVC (17±5.5 mm Hg; P<0.001). During a mean follow-up of 43 months, 40 patients were transplanted and 111 died. A total of 285 (75%) patients had an FHVP-IVC difference within ±2 mm Hg (no discrepancy) and 95 (25%) patients<-2 mm Hg or >2 mm Hg (discrepancy). In patients without discrepancy, 16 mm Hg was the best cut-off value predicting survival, independently of being calculated as HVPG-Free or HVPG-IVC. However, in those patients with discrepancy, 16 mm Hg was still the best cut-off value for HVPG-Free, but not for HVPG-IVC, among which 25 patients (26%) were misclassified regarding their risk of OLT/death.Given that WHVP-FHVP was more accurate in assessing prognosis than WHVP-IVC, HVPG should be calculated as the gradient between WHVP and FHVP, but not with IVC, in order to optimize its prognostic value and in identifying different risk population.
Heavy metal to lower the pressure?
Authors: R. Kohler
Journal: Cardiovascular Research (2012)

This editorial refers to ‘Tungstate activates BK channels in a β subunit- and Mg2+-dependent manner: relevance for arterial vasodilatation’ by A.I. Fernandez-Marino et al ., doi:10.1093/cvr/cvs139. 

Activation of the large conductance, Ca2+-dependent K+ channel [KCa1.1+β-subunits, generally known as the Big K (BK) or maxi K channel] is an important negative feedback on depolarization and Ca2+-induced contraction of smooth muscle and thus arterial vasoconstriction ( Figure 1 ). Intriguingly, altered function of BK and/or polymorphism in human BK α- and β-subunit genes have been associated with hypertension,1,2 and, from the therapeutic perspective, it is generally believed or hoped that improving BK channel function helps to ease vasodilation and to lower blood pressure in hypertension. The study by Fernandez-Marino et al .3 demonstrates that the heavy metal salt tungstate has vasodilator capabilities by stimulating BK activity ( Figure 1 ). At the molecular level, the authors showed that this positive gating modulation is conferred by the β1-subunit of the BK channel complex and interactions with the magnesium control of channel activity. Hence, the study makes a significant contribution to a better understanding of the regulation of BK channels by a heavy metal salt. From the translational perspective, the study fosters the potential utility of tungstate as a new type of antihypertensive ‘drug’, …
ATF3 Protects against Renal Ischemia-Reperfusion Injury
Authors: Takumi Yoshida, Hidekazu Sugiura, Michihiro Mitobe, Ken Tsuchiya, Satsuki Shirota, Sayoko Nishimura, Shunji Shiohira, Hiroshi Ito, Kiyoshi Nobori, Steven R Gullans, Takashi Akiba, Kosaku Nitta
Journal: Journal of the American Society of Nephrology (2008)

Oxidative stress-induced cell death plays a major role in the progression of ischemic acute renal failure. Using microarrays, we sought to identify a stress-induced gene that may be a therapeutic candidate. Human proximal tubule (HK2) cells were treated with hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>) and RNA was applied to an Affymetrix gene chip. Five genes were markedly induced in a parallel time-dependent manner by cluster analysis, including activating transcription factor 3 (ATF3), p21<sup>WAF1/CiP1</sup> (p21), CHOP/GADD153, dual-specificity protein phosphatase, and heme oxygenase-1. H<sub>2</sub>O<sub>2</sub> rapidly induced ATF3 approximately 12-fold in HK2 cells and approximately 6.5-fold in a mouse model of renal ischemia-reperfusion injury. Adenovirus-mediated expression of ATF3 protected HK2 cells against H<sub>2</sub>O<sub>2</sub>-induced cell death, and this was associated with a decrease of p53 mRNA and an increase of p21 mRNA. Moreover, when ATF3 was overexpressed in mice <i>via</i> adenovirus-mediated gene transfer, ischemia-reperfusion injury was reduced. In conclusion, ATF3 plays a protective role in renal ischemia-reperfusion injury and the mechanism of the protection may involve suppression of p53 and induction of p21.
Transplantation behavior of A.TH and A.TL T-cell lymphomas in congenic resistant and hybrid strains.
Authors: J W Goding, N L Warner
Journal: The Journal of Experimental Medicine (1975)

Seven spontaneously arising T-cell lymphomas originating in A.TH or A.TL mice, which are congenic for the immune response gene (I) chromosomal segment were described. When transplanted into partner strains which were incompatible at the I region, the tumors were rapidly rejected. Rejection was proposed to be due to the presence of antigens controlled by I-region genes.
Right Ventricular Function and Failure
Authors: Norbert F. Voelkel, Robert A. Quaife, Leslie A. Leinwand, Robyn J. Barst, Michael D. McGoon, Daniel R. Meldrum, Jocelyn Dupuis, Carlin S. Long, Lewis J. Rubin, Frank W. Smart, Yuichiro J. Suzuki, Mark Gladwin, Elizabeth M. Denholm, Dorothy B. Gail
Journal: Circulation (2006)
Does Aggressive Surgery Only Benefit Patients With Less Advanced Ovarian Cancer? Results From an International Comparison Within the SCOTROC-1 Trial
Authors: Simon C. Crawford, Paul A. Vasey, Jim Paul, Andrea Hay, Jo A. Davis, Stan B. Kaye
Journal: Journal of Clinical Oncology (2005)

Purpose Studies indicate that ovarian cancer patients who have been optimally debulked survive longer. Although chemotherapy has been variable, they have defined standards of care. Additionally, it is suggested that patients from the United Kingdom (UK) have inferior survival compared with some other countries. We explored this within the context of a large, international, prospective, randomized trial of first-line chemotherapy in advanced ovarian cancer (docetaxel-carboplatin v paclitaxel-carboplatin; SCOTROC-1). The Scottish Randomised Trial in Ovarian Cancer surgical study is a prospective observational study examining the impact on progression-free survival (PFS) of cytoreductive surgery and international variations in surgical practice. Patients and Methods One thousand seventy-seven patients were recruited (UK, n = 689; Europe, United States, and Australasia, n = 388). Surgical data were available for 889 patients. These data were analyzed within a Cox model. Results There were three main observations. First, more extensive surgery was performed in non-UK patients, who were more likely to be optimally debulked (≤ 2 cm residual disease) than UK patients (71.3% v 58.4%, respectively; P &lt; .001). Second, optimal debulking was associated with increased PFS mainly for patients with less extensive disease at the outset (test for interaction, P = .003). Third, UK patients with no visible residual disease had a less favorable PFS compared with patients recruited from non-UK centers who were similarly debulked (hazard ratio = 1.85; 95% CI, 1.16 to 2.97; P = .010). This observation seems to be related to surgical practice, primarily lymphadenectomy. Conclusion Increased PFS associated with optimal surgery is limited to patients with less advanced disease, arguing for case selection rather than aggressive debulking in all patients irrespective of disease extent. Lymphadenectomy may have beneficial effects on PFS in optimally debulked patients.
Vagal nerve stimulation releases vasoactive intestinal peptide which significantly increases coronary artery blood flow
Authors: L Feliciano
Journal: Cardiovascular Research (1998)

To determine the effects of vasoactive intestinal peptide (VIP), released endogenously from cardiac vagal nerves, on coronary artery blood flow (CBF).We determined the effects of vagal nerve stimulation (VNS) at frequencies of 10, 15, 20, and 30 Hz on left circumflex coronary artery (LCx) blood flow. The increases in CBF during VNS were compared with the increases in CBF produced by exogenous VIP and also nitroglycerin (NTG). In 18 anesthetized open chest mongrel dogs, we blocked the muscarinic and beta-adrenergic receptors with atropine and propranolol. We controlled heart rate and aortic pressure by right atrial pacing and an arterial reservoir. CBF was measured in the LCx with a Doppler flow probe. A 25 gauge catheter was placed in the proximal LCx to inject the VIP receptor antagonist [4Cl-D-Phe6Leu17]VIP, VIP, NTG, or vehicle. CBF, aortic and ventricular pressures, ventricular contractility (+dp/dt(max)) and relaxation (-dp/dt(min)) and the EKG were measured.VNS (0.5 ms, 20 V, 5 min.) at 20 Hz maximally increased CBF by 62 +/- 14% at 5 min from 71 +/- 10 to 115 +/- 19 ml/min (p < 0.01). VNS at 10, 15, and 30 Hz increased CBF by 6 +/- 1%, 24 +/- 5%, and 24 +/- 7%, respectively (all p < 0.05 vs control). Following 20 Hz VNS, CBF returned toward the baseline over 30 min. Aortic and left ventricular (LV) pressures, LV +dp/dt(max) and LV-dp/dt(min) did not significantly change. After the direct administration of [4Cl-D-Phe6Leu17]VIP into the LCx, VNS increased CBF by only 10 +/- 4% (p = NS). Exogenous VIP, in doses of 9.0 x 10(-11) to 2.1 x 10(-9) mol, increased CBF by 106 +/- 17% to 169 +/- 17% (all p < 0.01 vs control). NTG, in doses of 2.2 x 10(-8) to 1.7 x 10(-7) mol, increased CBF by 101 +/- 15% to 169 +/- 20% (all p < 0.01 vs control). These increases in CBF persisted during the 1 to 2 min injection period and returned to the baseline within 5 min. Neither VIP nor NTG significantly changed the heart rate, aortic or LV pressures, LV +dp/dt(max) or LV -dp/dt(min). VNS at 20 Hz, exogenous VIP, 9.0 x 10(-11) mol, and exogenous NTG, 2.2 x 10(-8) to 4.4 x 10(-8) mol, produced equivalent increases in CBF by analysis of variance determination.The present experiments suggest that VNS releases VIP which directly dilates coronary arteries and significantly increases coronary artery blood flow.
Matching Older Kidneys with Older Patients Does Not Improve Allograft Survival
Authors: Bertram L. Kasiske, Jon Snyder
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Centers may restrict the use of some donor kidneys on the belief that overall graft survival is improved by giving older kidneys to older recipients and vice versa. The prevalence and the effect on graft survival (determined by death, return to dialysis, or retransplantation) of this practice among 74,297 first cadaver kidney transplantations in 1988 to 1998 was examined by using data from the United States Renal Data System. Giving older kidneys to older recipients is common; recipients ≥55 yr old received donor kidneys that were ≥55 yr old 46.2% more often than expected, but they received kidneys that were 18 to 29 yr old 33.6% less often than expected (χ2P < 0.0001). Both recipient and donor age have important effects on graft survival, although the effects of donor age are much stronger than those of recipient age. Compared with recipients 18 to 29 yr old, recipients ≥55 yr old were 25% (95% confidence interval, 15 to 35%, P < 0.0001) more likely to have graft failure (adjusted for donor age and other risk factors). On the other hand, donor kidneys ≥55 yr old were 78% (95% confidence interval, 58 to 99%, P < 0.0001) more likely to fail compared with kidneys 18 to 29 yr old. However, giving older kidneys to older recipients had little independent effect on graft survival, once the intrinsic effects of recipient and donor age were taken into account. For example, transplanting donor kidneys ≥55 yr old into recipients ≥55 yr old reduced the risk of graft failure only −6% (95% confidence interval, −18 to 8%, P = 0.3923) after the independent effects of donor and recipient age per se were taken into account. Thus, giving older kidneys to older recipients is a common practice that does not improve overall graft survival.
Prognostic Significance of Focal Lesions in Whole-Body Magnetic Resonance Imaging in Patients With Asymptomatic Multiple Myeloma
Authors: Jens Hillengass, Kerstin Fechtner, Marc-André Weber, Tobias Bäuerle, Sofia Ayyaz, Christiane Heiss, Thomas Hielscher, Thomas M. Moehler, Gerlinde Egerer, Kai Neben, Anthony D. Ho, Hans-Ulrich Kauczor, Stefan Delorme, Hartmut Goldschmidt
Journal: Journal of Clinical Oncology (2010)

With whole-body magnetic resonance imaging (wb-MRI), almost the whole bone marrow compartment can be examined in patients with monoclonal plasma cell disease. Focal lesions (FLs) detected by spinal MRI have been of prognostic significance in symptomatic multiple myeloma (sMM). In this study, we investigated the prognostic significance of FLs in wb-MRI in patients with asymptomatic multiple myeloma (aMM).Wb-MRI was performed in 149 patients with aMM. The prognostic significance of the presence and absence, as well as the number, of FLs for progression into sMM was analyzed.FLs were present in 28% of patients. The presence per se of FLs and a number of greater than one FL were the strongest adverse prognostic factors for progression into sMM (P < .001) in multivariate analysis. A diffuse infiltration pattern in MRI, a monoclonal protein of 40 g/L or greater, and a plasma cell infiltration in bone marrow of 20% or greater were other adverse prognostic factors for progression-free survival in univariate analysis.We recommend use of wb-MRI for risk stratification of patients with asymptomatic multiple myeloma.
AAV2 Vector Harboring a Liver-Restricted Promoter Facilitates Sustained Expression of Therapeutic Levels of α-Galactosidase A and the Induction of Immune Tolerance in Fabry Mice
Authors: Robin J Ziegler, Scott M Lonning, Donna Armentano, Chester Li, David W Souza, Maribeth Cherry, Christine Ford, Christine M Barbon, Robert J Desnick, Guangping Gao, James M Wilson, Richard Peluso, Simon Godwin, Barrie J Carter, Richard J Gregory, Samuel C Wadsworth, Seng H Cheng
Journal: Molecular Therapy (2003)

The successful application of gene therapy for the treatment of genetic diseases such as Fabry is reliant on the development of vectors that are safe and that facilitate sustained expression of therapeutic levels of the transgene product. Here, we report that intravenous administration of a recombinant AAV2 vector encoding human alpha-galactosidase A under the transcriptional control of a liver-restricted enhancer/promoter (AAV2/DC190-alphagal) generated significantly higher levels of expression in BALB/c and Fabry mice than could be realized using the ubiquitous CMV promoter (AAV2/CMVHI-alphagal). Moreover, AAV2/DC190-alphagal-mediated hepatic expression of alpha-galactosidase A was sustained for 12 months in BALB/c mice and was associated with a significantly reduced immune response to the expressed enzyme. Subsequent challenge of the AAV2/DC190-alphagal-treated animals with recombinant human alpha-galactosidase A at 6 months failed to elicit the production of anti-alpha-galactosidase A antibodies, suggesting the induction of immune tolerance in these animals. The levels of expression attained with AAV2/DC190-alphagal in the Fabry mice were sufficient to reduce the abnormal accumulation of globotriaosylceramide in the liver, spleen, and heart to basal levels and in the kidney by approximately 40% at 8 weeks. Together, these results demonstrate that AAV2-mediated gene transfer that limits the expression of alpha-galactosidase A to the liver may be a viable strategy for treating Fabry disease.
Alcohol and violence.
Authors: D W Yates, H Chambers
Journal: BMJ (1987)

alone.Four weeks later she was discharged from hospital taking 62 IU daily.The chloroquine dose was gradually reduced, and she remained respon- sive to subcutaneous insulin.The rarityoftrue subcutaneous insulin resistance has been emphasised.3The patient reported on by Blazaretalhad accelerated insulin degradation in subcutaneous fat but also showed severe resistance to intravenous insulin.2There is evidence that, in addition to its action on hepatocyte receptors and receptor mediated degradation, chloroquine also inhibits lysosomal degradation in human skeletal muscle4 and fibroblasts5 and that it inhibits adipocyte insulin degradation in vivo.6 Chloro- quine's action may help to explain the pathogenesis of this rare syndrome as well as being useful in its management.
Statement on Exercise: Benefits and Recommendations for Physical Activity Programs for All Americans
Authors: Gerald F. Fletcher, Gary Balady, Steven N. Blair, James Blumenthal, Carl Caspersen, Bernard Chaitman, Stephen Epstein, Erika S. Sivarajan Froelicher, Victor F. Froelicher, Ileana L. Pina, Michael L. Pollock
Journal: Circulation (1996)
Vascular Endothelial Growth Factor Receptor-1 Activation Mediates Epithelial to Mesenchymal Transition in Human Pancreatic Carcinoma Cells
Authors: Anthony D. Yang, E. Ramsay Camp, Fan Fan, Lanlan Shen, Michael J. Gray, Wenbiao Liu, Ray Somcio, Todd W. Bauer, Yan Wu, Daniel J. Hicklin, Lee M. Ellis
Journal: Cancer Research (2006)

Abstract Our laboratory has shown that vascular endothelial growth factor receptor-1 (VEGFR-1) expression on human pancreatic cancer cell lines mediates cell migration and invasion. Because epithelial to mesenchymal transition (EMT) also plays a role in cell motility by altering the cell phenotype and morphology, we hypothesized that VEGFR-1 activation induces molecular alterations that mediate EMT. Our treatment of the human pancreatic cancer cell line L3.6pl with the VEGFR-1 ligands VEGF-A and VEGF-B led to morphologic changes characteristic of EMT, including loss of polarity, increased intercellular separation, and the presence of pseudopodia. Immunofluorescent staining with antibodies to E-cadherin and β-catenin showed that VEGFR-1 activation led to translocation of E-cadherin and β-catenin from their usual cell membrane–bound location to the cytoplasm and nucleus, respectively. Western blotting showed that VEGFR-1 activation led to decreased expression of the epithelial markers E-cadherin and plakoglobin, increased expression of the mesenchymal markers vimentin and N-cadherin, and increased nuclear expression of β-catenin. Pretreatment of tumor cells with a VEGFR-1 blocking antibody inhibited the VEGFR-1-induced immunohistochemical and molecular changes in E-cadherin. VEGFR-1 activation led to an increase in expression of the EMT-associated transcription factors Snail, Twist, and Slug. The changes mediated by VEGFR-1 in this pancreatic carcinoma cell line are highly consistent with the changes characteristic of EMT. Given our previous finding of VEGFR-1-mediated tumor cell invasion and migration in pancreatic carcinoma cells, we hypothesize that VEGFR-1 plays a role in tumor progression in pancreatic cancer through the induction of EMT. (Cancer Res 2006; 66(1): 46-51)
Identification of ASF/SF2 as a Critical, Allele-Specific Effector of the Cyclin D1b Oncogene
Authors: Nicholas A. Olshavsky, Clay E.S. Comstock, Matthew J. Schiewer, Michael A. Augello, Terry Hyslop, Claudio Sette, Jinsong Zhang, Linda M. Parysek, Karen E. Knudsen
Journal: Cancer Research (2010)

The cyclin D1b oncogene arises from alternative splicing of the CCND1 transcript, and harbors markedly enhanced oncogenic functions not shared by full-length cyclin D1 (cyclin D1a). Recent studies showed that cyclin D1b is selectively induced in a subset of tissues as a function of tumorigenesis; however, the underlying mechanism(s) that control tumor-specific cyclin D1b induction remain unsolved. Here, we identify the RNA-binding protein ASF/SF2 as a critical, allele-specific, disease-relevant effector of cyclin D1b production. Initially, it was observed that SF2 associates with cyclin D1b mRNA (transcript-b) in minigene analyses and with endogenous transcript in prostate cancer (PCa) cells. SF2 association was altered by the CCND1 G/A870 polymorphism, which resides in the splice donor site controlling transcript-b production. This finding was significant, as the A870 allele promotes cyclin D1b in benign prostate tissue, but in primary PCa, cyclin D1b production is independent of A870 status. Data herein provide a basis for this disparity, as tumor-associated induction of SF2 predominantly results in binding to and accumulation of G870-derived transcript-b. Finally, the relevance of SF2 function was established, as SF2 strongly correlated with cyclin D1b (but not cyclin D1a) in human PCa. Together, these studies identify a novel mechanism by which cyclin D1b is induced in cancer, and reveal significant evidence of a factor that cooperates with a risk-associated polymorphism to alter cyclin D1 isoform production. Identification of SF2 as a disease-relevant effector of cyclin D1b provides a basis for future studies designed to suppress the oncogenic alternative splicing event.