tbuckley/cabot-search huggingface dataset:
Dual blockade of renin-angiotensin system
Authors: J. McCormack
Journal: BMJ (2001)

Editor—Mogensen et al interpret their results as showing that the combination of lisinopril plus candesartan was more effective than either agent alone at lowering blood pressure and reducing the urinary albumin:creatinine ratio over 24 weeks in patients with type 2 (non-insulin dependent) diabetes.1 They state, “our results . . . support this new and potentially highly beneficial therapeutic approach for the prevention of diabetic renal and vascular disease.”

The authors' interpretation of the renoprotective effect of the combination and its superiority in lowering blood pressure does not seem to be supported by the results. Several methodological issues in particular limit their interpretation.

Firstly, the authors state in the abstract that “the reduction in urinary albumin:creatinine ratio with combination treatment . . . was greater than with either candesartan . . . or lisinopril.” Table 4, however, shows that the difference in the albumin:creatinine ratio between lisinopril and the combination was not significant (P>0.20); they did not show that the combination was more effective than lisinopril alone. The P value for the difference between candesartan and the combination was 0.04. As numerous statistical tests were done and no correction for multiple testing was applied we question whether a P value of 0.04 is significant.

Secondly, the authors report that the combination produced increases in creatinine and urea concentrations and a decrease in creatinine clearance at 24 weeks. These changes at best should be going in the opposite direction, or at least be no different if the combination is more renoprotective.

Thirdly, from a methodological perspective, two factors need explaining.

Firstly, patients received combination treatment only during weeks 12-24. Inexplicably, the authors compared the effects of the combined treatment (at 24 weeks) with baseline data (week 0). Secondly, 53 patients (27%) who had been enrolled in the trial were excluded from these comparisons because their diastolic pressures had been reduced to <80 mm Hg at week 12 with single treatment.

In essence, the authors compared patients who received the combination (including carry-over effects from 12 weeks of single treatment) with patients who had the least response to single treatment. This is a biased comparison, and the authors should have compared single and combination treatment from 12 to 24 weeks, not from baseline. Presumably, the 53 patients were excluded because it was deemed unsafe or unnecessary to reduce their blood pressures further.

It would be of concern if clinicians concluded from this study that it is beneficial to use the combination at the outset of treatment.
Uncommon EGFR Exon 19 Mutations Confer Gefitinib Resistance in Advanced Lung Adenocarcinoma
Authors: Simona Coco, Anna Truini, Irene Vanni, Carlo Genova, Camillo Rosano, Maria Giovanna Dal Bello, Angela Alama, Roberta Venè, Erika Rijavec, Giulia Barletta, Federica Biello, Francesco Boccardo, Francesco Grossi
Journal: Journal of Thoracic Oncology (2015)
Abstract 948: An Allosteric Mechanism for Drug Block of a Cardiac Potassium Channel
Authors: Tao Yang, Jarrod A Smith, Jens Meiler, Tammy L Wingo, Hideaki Kanki, Brenda Leake, Charles R Sanders, Jeffrey R Balser, Dan M Roden
Journal: Circulation (2007)

Background: A common mechanism for block of ion channels is current inhibition by drug binding to residues - notably in S6 - within the permeating pore. Open state block is commonly observed. Methods and Results: In this study, we used a combination of alanine/cysteine mutagenesis, patch clamp, and homology modeling to identify a novel allosteric mechanism for drug block of the human cardiac potassium channel KCNQ1 (the α-subunit encoding IKs). The initial mutagenesis experiments studied a total of 45 amino acid residues in the S6 segment (30 residues), and the proximal C-terminus (15 residues) of KCNQ1. Residues required for drug block were identified as alanine/cysteine mutants displaying &lt;50% block of expressed current (n=4 – 6 each) upon exposure to drug concentrations inhibiting wild-type current by ≥90% (quinidine 100 μm, clofilium 30 μm and L-7 10 μm). Among the 30 residues in S6, there were five (F332, F335, S338, A341 and G348) displaying such reduced block and in the proximal C-terminus, 5/15 were less sensitive, including F351 which was near-totally resistant (current decrease = 4±3%). Homology modeling of KCNQ1 based on the Kv1.2 structure unexpectedly suggested that F351 faces away from the permeating pore, arguing against pore block as the mechanism for drug inhibition of KCNQ1 current. In the open channel model, F351 lines a pocket that also includes L251 and V254 in S4–S5. The model allows drug access to this pocket, and alanine substitutions at both sites yielded potassium currents that were resistant to drug block (↓34±4% for L251A and ↓40±5% for V254A). Conclusion: These data strongly support a model in which open state block of this channel occurs not via binding to a site in the pore but rather by a novel allosteric mechanism, drug access to a side pocket generated in the open channel configuration and lined by S6 and S4/S5 residues.
Abstract 724: Synectin is Required for Normal PDGF Secretion and Smooth Muscle Cell Basic Science Recruitment
Authors: Julie M Paye, Thomas W Chittenden, Li-Kun Phng, Holger Gerhardt, Michael Simons
Journal: Circulation (2007)

Background: Synectin, a ubiquitously expressed scaffold and PDZ protein, has been shown to be a key regulator in the formation of arterial vasculature. Primary arterial endothelial cells isolated from synectin−/− mice exhibited defects in PDGF signaling that were not present in arterial synectin+/+ or either venous synectin+/+ or synectin−/− endothelial cells. Methods: To address the role of synectin in mural cell recruitment, retinas from synectin−/− (KO) and synectin+/+ (WT) mice were stained for isolectin and alpha-smooth muscle actin. To determine the mechanisms responsible for defective smooth muscle cells recruitment, primary arterial and venous endothelial (EC) and smooth muscle (SMC) cells were isolated from synectin+/+ and synectin−/− mice. Results: Examination of the retinal vasculature in synectin−/− mice demonstrated poor smooth muscle cell coverage of the forming arterial tree with a number of SMC cells sitting some distance away from the vessels, a defect reminiscent of retinal abnormalities observed in PDGF-B−/− mice. Western blot analysis of lysates from primary KO SMC demonstrated levels of PDGFR-β analogous to WT, although expression of PDGF-B was markedly reduced in lysates from arterial, but not venous, primary KO endothelial cells. Transduction of KO EC with an adenoviral synectin construct was sufficient to restore PDGF-B protein levels. Further, qPCR was used to determine whether defects in PDGF-B protein production were at the transcription or translation level. Interestingly, there was only a minor decrease in the amount of PDGF-B mRNA in KO compared to WT EC, suggesting that synectin deficiency has selectively affected post-transcriptional regulation of PDGF-B expression. Migration of WT and KO SMC in response to PDGF-B or conditioned media from WT and KO endothelial cells was also assessed to determine the cell type specificity of PDGF defects in KO mice. Conclusions: Synectin is required for post-transcriptional regulation of PDGF-B in endothelial cells. Deficits in PDGF-B secretion by synectin−/− endothelial cells result in inadequate smooth muscle recruitment and coverage of arterial vessels.
Taking Patients’ Narratives about Clinicians from Anecdote to Science
Authors: Mark Schlesinger, Rachel Grob, Dale Shaller, Steven C. Martino, Andrew M. Parker, Melissa L. Finucane, Jennifer L. Cerully, Lise Rybowski
Journal: New England Journal of Medicine (2015)

When choosing clinicians, patients often rely on comments available on consumer websites. The authors argue that public reporting of standardized patient satisfaction surveys could be improved if they were augmented by narrative accounts of patients' experiences.
Abstract 1881: Association of New-Onset Left Bundle Branch Block with Cardiovascular Morbidity and Mortality in Hypertensive Patients with Left Ventricular Hypertrophy: The LIFE study
Authors: Zhi Bin Li, Silvana Cicala, Kristian Wachtell, Hans Ibsen, Markku S. Nieminen, Sverker Jern, Peter M. Okin, Stevo Julius, Sverre E. Kjeldsen, Bjorn Dahlof, Richard B. Devereux
Journal: Circulation (2006)

Background : Whether new-onset left bundle branch block (LBBB) is associated with increased cardiovascular morbidity and mortality in treated hypertensive patients is unknown.   Object : To assess cardiovascular morbidity and mortality associated with new-onset LBBB in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study among hypertensive patients with electrocardiographic left ventricular hypertrophy (LVH).   Methods:  Hypertensive patients with LVH by Cornell voltage-duration product or Sokolow-Lyon voltage criteria on screening electrocardiograms were randomized to a mean of 4.8 years of losartan- or atenolol-based treatment. electrocardiograms were read at a central laboratory; Minnesota code 7.1 identified LBBB. Only participants without LBBB on LIFE study baseline electrocardiograms were included in the current study.   Results : The electrocardiograms in LIFE study annual follow-up evaluations identified 296 patients (143 or 48.3% women) with and 8277 patients (4458 or 53.9% women) without new-onset LBBB. New-onset LBBB was associated with older age (70.0±6.2 vs. 67.3±7.0 years), higher sex-adjusted Cornell voltage (30.7±7.9 vs. 27.2±7.1) and higher prevalence of cardiovascular disease (35.8% vs. 24.2%)(all p   Conclusion:  Among hypertensive patients with electrocardiographic LVH, new-onset LBBB independently identifies those at increased risk of developing subsequent congestive heart failure and myocardial infarction.
Abstract 15452: Carotid Magnetic Resonance Imaging and Ultrasound Intima-Media Thickness for the Prediction of Cardiovascular Events: the Multi-Ethnic Study of Atherosclerosis
Authors: Anna E Zavodni, Bruce A Wasserman, Robyn L McClelland, Antoinette S Gomes, Aaron R Folsom, Joseph F Polak, Joao A Lima, David A Bluemke
Journal: Circulation (2011)

Introduction: Carotid MRI has been shown to accurately depict wall thickness and plaque components such as lipid core. Whereas carotid IMT by ultrasound has been validated to predict cardiovascular...
Abstract 12102: Pharmacologically Induced Hypothermia with Cannabinoid Receptor Agonist Improve the Outcome of Cardiopulmonary Resuscitation
Authors: Shijie Sun, Yinlun Weng, Fengqing Song, Tao Yu, Sung Phil Chung, Wanchun Tang, Max H Weil
Journal: Circulation (2010)

Early application of therapeutic hypothermia and rapid achievement of target cooling temperature are the key factors for improving outcomes following CPR. Current available techniques for inducing ...
Blood pressure variability and the outcome in acute intracerebral haemorrhage: post-hoc analysis of the INTERACT2 randomised controlled trial.
Authors: L. Manning, Y. Hirakawa, A. Arima, X. Wang, J. Chalmers, J. Wang, Richard Lindley, Emma Heeley, C Delcourt, Bruce Neal, P. Lavados, S. M. Davis, C. Tzourio, Y. Huang, C. Stapf, Mark Woodward, P. M. Rothwell, T. G. Robinson, Craig S. Anderson, Interact Investigators
Journal: The Lancet Neurology (2014)
Quantitative Analysis of Skin Flap Blood Flow in the Rat Using Laser Doppler Velocimetry
Authors: Nicholas J Marks
Journal: Journal of the Royal Society of Medicine (1985)

Two experiments carried out on rat skin flaps are described, where microvascular flow has been measured noninvasively by a laser Doppler velocimeter. Using this technique it is possible to define the limits of an axial pattern flap in terms of microvascular flow; this was found to increase when the flap is elevated. 'Random-pattern' perfusion is defined by a fall in flow. This recovers sequentially along the flap, and at a constant rate at all sites. A differential in microvascular perfusion is thus maintained along a random-pattern flap for at least the first postoperative week. In a second experiment it is shown that there appears to be a linear relationship between the reduction in skin blood flow in a random-pattern flap and the distance from the base at which the measurements are made. It is suggested that these data support the view that the blood flow in a skin flap recovers primarily from its base rather than via peripheral neovascularization, and that this is due to vascular collaterals opening within the flap rather than to a relaxation of sympathetic tone.
Tooth pulp may be a good source of stem cells
Authors: Deborah Josefson
Journal: BMJ (2003)

Researchers from the United States and Australia have found that deciduous teeth have robust stem cells in their dental pulp. The finding is important, because such teeth may serve as an easily obtainable alternative to embryonic stem cells, the use of which has proved controversial.

Moreover, like umbilical cord blood, they may serve as a ready source of autologous and bankable stem cells, the study says (published online before print in the Proceedings of the National Academy of Science of the United States of America, www.pnas.org).

Stem cells have the ability to differentiate into a wide variety of cell types. Theoretically they can be grown into various organs, as well as into nerve, bone, or haematopoeitic cells.

The researchers, led by Dr Songtao Shi, a paediatric dentist based at the National Institute of Dental and Craniofacial Research, Bethesda, Maryland, isolated stem cells from the baby teeth of children aged seven or eight years.


The researchers found that pulp from incisor teeth had more stem cell activity than molars and that between 12 and 20 cells from deciduous incisors were stem cells. 





PASCAL GOETGHELUCK/SPL
Acetylcysteine and Renal Function Following Coronary Angiographic Procedures—Reply
Authors: Jay Kay
Journal: JAMA (2003)

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Co-delivery of VEGF and Bcl-2 dual-targeted siRNA polymer using a single nanoparticle for synergistic anti-cancer effects in vivo
Authors: So Jin Lee, Simmyung Yook, Ji Young Yhee, Hong Yeol Yoon, Myung-Goo Kim, Sook Hee Ku, Sun Hwa Kim, Jae Hyung Park, Ji Hoon Jeong, Ick Chan Kwon, Seulki Lee, Hyukjin Lee, Kwangmeyung Kim
Journal: Journal of Controlled Release (2015)
Abstract 246: Chest Compression Rates Used During Out-of-Hospital Cardiopulmonary Resuscitation in Nine Resuscitation Outcomes Consortium Regional Sites
Authors: Ahamed H Idris, Patrick Nichols, Danielle Schroeder, Siobhan Everson-Stewart, Judy L Powell, Clifton W Callaway, Laurie Morrison, Tom P Aufderheide, Tom Rea, Dianne Atkins, Robert Berg, Blair Bigham, Dan Davis, Ian Stiell, George Sopko, Graham Nichol
Journal: Circulation (2010)

Background: The current American Heart Association guidelines for cardiopulmonary resuscitation (CPR) recommend using a chest compression rate of 100 compressions/min. Some animal models of CPR hav...
Abstract 9519: Acute Myocardial Ischemia Results in Renal Dysfunction via Systemic and Local Inflammation and Oxidant Stress, and LOX-1 Abrogation Attenuates This Phenomenon
Authors: Jingjun Lu, Abhishek Deshmukh, Xianwei Wang, Sona Mitra, Wenze Wang, Harisk Muniyappa, Changping Hu, Kumuda Das, Tatsuya Sawamura, Jawahar Mehta
Journal: Circulation (2011)

Aims It is assumed that acute myocardial infarction (MI) affects renal function.We tested this assumption in mice subjected to left coronary artery (LCA) occlusion. We also tested the hypothesis that LOX-1 deletion may inhibit systemic inflammation and oxidant stress and reduce renal dysfunction following MI. Methods Wild-type (WT) and LOX-1 KO mice were subjected to total and permanent LCA occlusion resulting in acute and extensive MI.Cardiac function (LVEF) was analyzed by echocardiography at days 3 and 21 post-MI.Renal function (serum BUN and creatinine) and morphology (H&amp;E and trichrome staining) were assessed at same time points.The pro-inflammatory signals and markers of fibrosis were measured by Western blotting in the renal tissues. Results On day 3 after LCA ligation, there was a marked rise in pro-inflammatory cytokines in circulation (Multiplex system®). Importantly, there was a decline in renal function in association with &gt;2-fold increase in renal mass,swelling of renal gomeruli and tubules and mild fibrosis in the renal medulla. There was a significant increase in the expression IL- 1β and VCAM-1, LOX-1, NADPH oxidase, and markers of fibrosis (collagen IV, procollagen-I and fibronectin) in renal tissues. On day 21, renal size was smaller, renal function and morphology were improved except for more fibrosis, and signals of inflammation and oxidant stress were less marked (P&lt;0.05 vs. day 3). Deletion of LOX-1 resulted in a marked decline in systemic and renal pro-inflammatory and oxidant stress markers(all P&lt;0.05 vs. wild-type mice) and better renal function. Cardiac function as well as survival were better in LOX-1 KO mice than in the wild-type mice (P&lt;0.01) - all subjected to total LCA occlusion. Conclusion We demonstrate that acute MI results in renal dysfunction and histologic abnormalities reminiscent of acute injury to the kidneys. LOX-1 deletion by reducing pro-inflammatory and pro-oxidant signals results in significantly less renal dysfunction.
Abstract 8378: Novel System for the Molecular Imaging of Atherosclerotic Plaque with 68Ga-DOTA-ApoA-I Mimetic Peptide (-FAMP)
Authors: Eiji Yahiro, Yoshinari Uehara, Koki Hasegawa, Emi Kawachi, Tsuneo Yano, Yasuyoshi Watanabe, Shin-ichiro Miura, Keijiro Saku
Journal: Circulation (2011)

Cardiovascular disease is the leading cause of death, and atherosclerosis is a chronic, progressive disease with a long asymptomatic phase. Currently, most diagnostic modalities for atherosclerosis...
Abstract 5635: Negative Thinking: A Modifiable Target for the Treatment of Depressive Symptoms in Patients with Heart Failure
Authors: Rebecca L Dekker, Terry A Lennie, Ann R Peden, Misook L Chung, Jia-Rong Wu, Debra K Moser
Journal: Circulation (2008)

Background : The adverse effects of depressive symptoms on mortality and morbidity in patients with HF have been well described. The next step is to identify modifiable predictors of depressive symptoms that can be targeted for intervention. Negative thinking, a process of self-critical cognition, has been associated with depressed mood, which suggests it may be a modifiable target for intervention. However, it is not known whether negative thinking is independently related to depressive symptoms in patients with HF.   Purpose :  To describe the level of negative thinking among patients with HF.  To determine whether negative thinking is a predictor of depressive symptoms in patients with HF.   Methods : In this cross-sectional, descriptive study, 154 patients (61±12 years, 31% female, 52% NYHA Class III/IV) were recruited from an outpatient HF clinic. Negative thinking was measured with the Crandell Cognitions Inventory. Depressive symptoms were measured using the Beck Depression Inventory-II (BDI). Multiple linear regression was used to determine whether negative thinking is an independent predictor of depressive symptoms.   Results : The mean level of negative thinking was 60 ± 26, which is higher than the reported mean of 45 ± 8 for non-depressed, normal controls. The prevalence of clinically significant depressive symptoms (BDI >13) was 33%. Patients with depressive symptoms had substantially higher levels of negative thinking compared to patients without depressive symptoms (83 ± 27 vs. 49 ± 17,  p   p     Conclusion:  Our findings suggest that negative thinking plays a major role in the manifestation of depressive symptoms in patients with HF. Interventions that target the reduction of negative thinking may reduce depressive symptoms in patients with HF.
Abstract 38: ERK5 inhibitor XMD8-92 for malignant mesothelioma treatment: A preclinical study
Authors: Arti Shukla, Joyce Thompson, Anurag Shukla, Alan Leggett, Maximilian MacPherson, Stacie Beuschel
Journal: Cancer Research (2015)

Abstract Malignant mesothelioma (MM) is an aggressive cancer in dire need of successful treatment. We are first to demonstrate that Extracellular signal regulated kinase 5 (ERK5) plays an important role in MM pathogenesis (Clinical Cancer Research, 19, 2013). In this study we used genetically manipulated (ERK5 inhibited) MM cell lines to show that MM tumorigenesis is influenced by ERK5. In the present study we used recently discovered specific ERK5 inhibitor (XMD8-92) to show that it regulates MM tumor growth both in vitro and in vivo. First, we show that XMD8-92 inhibits ERK5 phosphorylation in 3 out of 4 MM cell lines showing constitutive activation of ERK5. Next, time and dose dependent study demonstrated significant cytotoxicity of XMD8-92 on 3 different MM cell lines. We also showed that soft agar colony forming efficiency of H2373 MM cells was significantly reduced in response to XMD8-92 treatment. Furthermore, in vivo studies using syngeneic mouse model of intraperitoneal mesothelioma showed that XMD8-92 treatment (50 mg/kg, ip, 1x daily for 3 weeks) resulted in significant decreases in tumor weights as compared to vehicle treated mice. Total and differential cell counts in peritoneal lavage fluid (PLF) were also inhibited by XMD8-92 suggesting the role of inflammation in MM tumor growth and their inhibition by ERK5 inhibitor. Cytokine profile assessment in PLF demonstrated the reduced levels of VEGF and IL-6 in XMD8-92 treated animals as compared to control animals receiving saline. FGF2, MCP-1, G-CSF, KC and RAGE levels were, however, not significantly impacted by the ERK5 inhibition. Taken together these data suggest that ERK5 inhibitor/ERK5 inhibition could be used for inhibiting the growth of MM tumors. Currently we are exploring the role of XMD8-92 alone as well as in combination with chemotherapeutic drugs for the treatment of MM using various mouse models. We are also exploring the role(s) of ERK5 inhibitor in inflammasome regulation by chemotherapeutics. This work is supported by NIEHS RO1 ES021110 and VCC/LCCRO grants. Citation Format: Arti Shukla, Joyce Thompson, Anurag Shukla, Alan Leggett, Maximilian MacPherson, Stacie Beuschel. ERK5 inhibitor XMD8-92 for malignant mesothelioma treatment: A preclinical study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 38. doi:10.1158/1538-7445.AM2015-38