tbuckley/cabot-search huggingface dataset:
Noninvasive Electrocardiographic Imaging of Arrhythmogenic Substrates in Humans
Authors: Yoram Rudy
Journal: Circulation Research (2013)

Cardiac excitation is determined by interactions between the source of electric activation (membrane depolarization) and the load that cardiac tissue presents. This relationship is altered in pathology by remodeling processes that often create a substrate favoring the development of cardiac arrhythmias. Most studies of arrhythmia mechanisms and arrhythmogenic substrates have been conducted in animal models, which may differ in important ways from the human pathologies they are designed to represent. Electrocardiographic imaging is a noninvasive method for mapping the electric activity of the heart in humans in real-world conditions. This review summarizes results from electrocardiographic imaging studies of arrhythmogenic substrates associated with human clinical arrhythmias. Examples include heart failure, myocardial infarction scar, atrial fibrillation, and abnormal ventricular repolarization.
DNA Aneuploidy and Integration of Human Papillomavirus Type 16 E6/E7 Oncogenes in Intraepithelial Neoplasia and Invasive Squamous Cell Carcinoma of the Cervix Uteri
Authors: Peter Melsheimer, Svetlana Vinokurova, Nicolas Wentzensen, Gunther Bastert, Magnus von Knebel Doeberitz
Journal: Clinical Cancer Research (2004)

Increasingly deregulated expression of the E6-E7 oncogenes of high-risk human papillomaviruses (HR-HPVs) has been identified as the major transforming factor in the pathogenesis of cervical dysplasia and derived cancers. The expression of these genes in epithelial stem cells first results in chromosomal instability and induces chromosomal aneuploidy. It is speculated that this subsequently favors integration of HR-HPV genomes into cellular chromosomes. This in turn leads to expression of viral cellular fusion transcripts and further enhanced expression of the E6-E7 oncoproteins. Chromosomal instability and aneuploidization thus seems to precede and favor integration of HR-HPV genomes.To prove this sequential concept, we analyzed here the sequence of events of DNA aneuploidization and integration in a series of HPV-16-positive cervical dysplastic lesions and carcinomas. Eighty-five punch biopsies of HPV-16-positive cervical lesions (20 CIN1/2, 50 CIN3, and 15 CxCa) were analyzed for DNA ploidy by DNA flow cytometry and for integration of HPV E6/E7 oncogenes using the amplification of papillomavirus oncogene transcripts assay, a reverse transcription-PCR method to detect integrate-derived human papillomavirus oncogene transcripts.DNA aneuploidy and viral genome integration were both associated with increasing dysplasia (P < 0.001, chi(2) test for trend). In addition, DNA aneuploidy was associated with increased viral integration (P < 0.01, Fisher's exact test). Nineteen of 20 (95%) lesions with integrated viral genomes had aneuploid cell lines; however, only 19 of 32 (59%) lesions with aneuploid cell lines had integrated viral genomes.These data support the hypothesis that aneuploidization precedes integration of HR-HPV genomes in the progression of cervical dysplasia. Accordingly, deregulated viral oncogene expression appears to result first in chromosomal instability and aneuploidization and is subsequently followed by integration of HR-HPV genomes in the affected cell clones.
Percutaneous In Situ Coronary Venous Arterialization
Authors: Stephen N. Oesterle, Nicolaus Reifart, Eugen Hauptmann, Motoya Hayase, Alan C. Yeung
Journal: Circulation (2001)

Abstract —Diffuse coronary artery disease is frequently untreatable by coronary artery bypass or angioplasty. Many such “no-option” patients have been subjects for trials of angiogenesis using growth factor manipulation or laser injury. We think these novel revascularization strategies are limited by insufficient inflow to putative areas of new microvasculature and thus seek a more mechanical solution. We report the use of a catheter-based system for arterializing the adjacent anterior cardiac vein in a patient with chronic total occlusion of the left anterior descending coronary artery. A composite catheter system (phased-array ultrasound imaging system mounted on a catheter with extendable nitinol needle) was used to deliver an exchange-length intracoronary guidewire from the proximal left anterior descending coronary artery into the parallel anterior interventricular vein. Using standard angioplasty techniques, a fistula was then constructed from the proximal artery to the coronary vein using a self-expanding connector. The proximal vein was blocked with a novel self-expanding “blocker,” thus precluding “steal” through the coronary sinus and forcing retroperfusion of the anterior wall. The procedure was completed without complication, and a follow-up angiogram at 3 months confirmed continued patency of the arteriovenous connection. This patient, who had severe angina before the procedure, has been asymptomatic for 12 months. Percutaneous in situ venous arterialization may be an effective therapy for diffuse, “untreatable” coronary disease by supplying a robust inflow of arterialized blood via retroperfusion to severely ischemic myocardium.
UK launches inquiry into safety of PIP breast implants
Authors: A. O'Dowd
Journal: BMJ (2012)

The UK government has launched a rapid review into the safety of a particular make of breast implants from France to try to reassure the 40 000 women in the country who have the implants. The French government has already announced that it will pay for the 30 000 women there who had the implants made by Poly Implant Prosthese (PIP) to have them removed as a preventive measure ( BMJ 2011;343:d8329, 29 Dec, doi:10.1136/bmj.d8329).

PIP went into administration last year, and use of its implants was banned amid worries that non-medical grade silicone had been used to make them.

Concerns emerged last month in the French media after it was claimed that the implants were linked to cases of cancer. Although …
Measurement characteristics of two asthma symptom diary scales for use in clinical trials
Authors: NC Santanello, BL Barber, TF Reiss, BS Friedman, EF Juniper, J Zhang
Journal: European Respiratory Journal (1997)

The measurement characteristics of two asthma symptom diary scales developed for use as health outcome measures in clinical trials of asthma therapy were investigated. A daytime diary scale was designed to capture the frequency and inconvenience of daytime asthma symptoms and their effects on activities, and a nocturnal asthma symptom diary scale was designed to capture awakenings with asthma symptoms. The internal consistency, reliability, validity and responsiveness of both asthma diary scales were assessed in 346 adult asthma patients in two placebo-controlled clinical trials of an investigational asthma therapy, a leukotriene biosynthesis inhibitor. The daytime symptom scale showed sufficient internal consistency (0.90-0.92), and the daytime and nocturnal symptom scales showed sufficient test retest reliability (0.69-0.87). Construct validity was demonstrated by generally moderate-to-strong correlations for changes in the diary scales with changes in other measures of asthma status, such as forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), and puffs of beta-agonist inhaler. Both scales demonstrated significant responsiveness to change in asthma due to therapy in one of the clinical trials. Based on these results, the daytime and nocturnal asthma symptom diary scales show measurement characteristics appropriate for use as asthma outcome measures in clinical trials of asthma therapy.
The Myth of Measurable Disease in Ovarian Cancer
Authors: Maurie Markman
Journal: Journal of Clinical Oncology (2003)

Article Tools EDITORIALS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2003.08.148 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12915591 The Myth of Measurable Disease in Ovarian Cancer Maurie MarkmanxMaurie MarkmanSearch for articles by this author Show More The Cleveland Clinic Taussig Cancer Center and the Department of Hematology/Medical Oncology, The Cleveland Clinic Foundation, Cleveland, OH https://doi.org/10.1200/JCO.2003.08.148 First Page Full Text PDF Figures and Tables © 2003 by American Society of Clinical Oncology
Hydralazine Reduces the Quantal Size of Secretory Events by Displacement of Catecholamines From Adrenomedullary Chromaffin Secretory Vesicles
Authors: José D. Machado, José F. Gómez, Gema Betancor, Marcial Camacho, Miguel A. Brioso, Ricardo Borges
Journal: Circulation Research (2002)

The effects of the antihypertensive agent hydralazine (1 to 100 nmol/L) on the exocytotic process of single adrenal chromaffin cells have been studied using amperometry. Hydralazine does not reduce the frequency of exocytotic spikes but rapidly slows the rate of catecholamine release from individual exocytotic events by reducing the quantal size of catecholamine exocytosis. Confocal and standard epifluorescence microscopy studies show that hydralazine rapidly accumulates within secretory vesicles. The blockade of the vesicular H+ pump with bafilomycin A1 inhibits hydralazine uptake. Experiments with permeabilized cells show that hydralazine displaces catecholamines from secretory vesicles. The drug also displaces vesicular Ca2+, as shown by fura-2 microfluorimetry. These data suggest that hydralazine acts, at least partially, by interfering with the storage of catecholamines. These effects of hydralazine occurred within seconds, and at the tissue concentrations presumably reached in antihypertensive therapy; these concentrations are a thousand times lower than those described for relaxing vascular tissues in vitro. We proposed that these novel effects could explain many of the therapeutic and side effects of this drug that are likely exerted in sympathetic nerve terminals.
Nuclear Factor of Activated T Cells Balances Angiogenesis Activation and Inhibition
Authors: Tetiana A. Zaichuk, Emelyn H. Shroff, Rebekah Emmanuel, Stephanie Filleur, Thomas Nelius, Olga V. Volpert
Journal: The Journal of Experimental Medicine (2004)

It has been demonstrated that vascular endothelial cell growth factor (VEGF) induction of angiogenesis requires activation of the nuclear factor of activated T cells (NFAT). We show that NFATc2 is also activated by basic fibroblast growth factor and blocked by the inhibitor of angiogenesis pigment epithelial–derived factor (PEDF). This suggests a pivotal role for this transcription factor as a convergence point between stimulatory and inhibitory signals in the regulation of angiogenesis. We identified c-Jun NH2-terminal kinases (JNKs) as essential upstream regulators of NFAT activity in angiogenesis. We distinguished JNK-2 as responsible for NFATc2 cytoplasmic retention by PEDF and JNK-1 and JNK-2 as mediators of PEDF-driven NFAT nuclear export. We identified a novel NFAT target, caspase-8 inhibitor cellular Fas-associated death domain–like interleukin 1β–converting enzyme inhibitory protein (c-FLIP), whose expression was coregulated by VEGF and PEDF. Chromatin immunoprecipitation showed VEGF-dependent increase of NFATc2 binding to the c-FLIP promoter in vivo, which was attenuated by PEDF. We propose that one possible mechanism of concerted angiogenesis regulation by activators and inhibitors may be modulation of the endothelial cell apoptosis via c-FLIP controlled by NFAT and its upstream regulator JNK.
A mechanism of ryanodine receptor modulation by FKBP12/12.6, protein kinase A, and K201
Authors: L. M. Blayney, J.-L. Jones, J. Griffiths, F. A. Lai
Journal: Cardiovascular Research (2009)

Our objective was to explore the functional interdependence of protein kinase A (PKA) phosphorylation with binding of modulatory FK506 binding proteins (FKBP12/12.6) to the ryanodine receptor (RyR). RyR type 1 or type 2 was prepared from rabbit skeletal muscle or pig cardiac muscle, respectively. In heart failure, RyR2 dysfunction is implicated in fatal arrhythmia and RyR1 dysfunction is associated with muscle fatigue. A controversial underlying mechanism of RyR1/2 dysfunction is proposed to be hyperphosphorylation of RyR1/2 by PKA, causing loss of FKBP12/12.6 binding that is reversible by the experimental inhibitory drug K201 (JTV519). Phosphorylation is also a trigger for fatal arrhythmia in catecholaminergic polymorphic ventricular tachycardia associated with point mutations in RyR2.Equilibrium binding kinetics of RyR1/2 to FKBP12/12.6 were measured using surface plasmon resonance (Biacore). Free Ca(2+) concentration was used to modulate the open/closed conformation of RyR1/2 channels measured using [(3)H]ryanodine binding assays. The affinity constant-K(A), for RyR1/2 binding to FKBP12/12.6, was significantly greater for the closed compared with the open conformation. The effect of phosphorylation or K201 was to reduce the K(A) of the closed conformation by increasing the rate of dissociation k(d). K201 reduced [(3)H]ryanodine binding to RyR1/2 at all free Ca(2+) concentrations including PKA phosphorylated preparations.The results are explained through a model proposing that phosphorylation and K201 acted similarly to change the conformation of RyR1/2 and regulate FKBP12/12.6 binding. K201 stabilized the conformation, whereas phosphorylation facilitated a subsequent molecular event that might increase the rate of an open/closed conformational transition.
Interleukin-6 is an important in vivo inhibitor of intestinal epithelial cell death in mice
Authors: Xiaoling Jin, Teresa A Zimmers, Zongxiu Zhang, Robert H Pierce, Leonidas G Koniaris
Journal: Gut (2008)

Background and aims Interleukin-6 (IL-6) is a well-recognised mediator of liver disease and regeneration. However, the in vivo effects of IL-6 on enterocytes and the intestinal tract have not been elucidated. We sought to determine the in vivo effects of IL-6 on enterocytes. Methods Murine models of increased or absent IL-6 were examined. Results Systemic, high-dose IL-6 administration to mice over 7–10 days resulted in intestinal hyperplasia with a ∼40% increase in small bowel mass and in intestinal villus height. No increase in crypt cell proliferation was noted. IL-6 administration was associated with induction of pSTAT3 in enterocytes along the lower and middle regions of villi but not in crypts. IL-6 administration was also associated with induction of anti-apoptotic proteins including pAKT, and FLIP along with decreased executor caspase activity and PARP cleavage. Pulse bromodeoxyuridine labelling demonstrated equivalent crypt cell proliferation rates but prolonged enterocyte lifespan and slowed enterocyte migration rates in IL-6 treated mice. Furthermore, IL-6 treated mice showed less intestinal injury and improved barrier function following ischaemia reperfusion of the small bowel. Conversely, Il6 null mice exhibited impaired recovery following massive enterectomy and increased apoptosis after 5-fluorouracil chemotherapy relative to wild-type controls. Conclusions IL-6 inhibited both constitutive and induced enterocyte cell death in vivo. Loss of IL-6 in mice resulted in increased activation of pro-apoptotic and necrotic pathways in enterocytes after injury. Therapies that augment IL-6 or its signalling pathways may help manage intestinal disorders associated with increased apoptosis, necrosis and gut injury.
Inflammation and Behavioral Symptoms After Breast Cancer Treatment: Do Fatigue, Depression, and Sleep Disturbance Share a Common Underlying Mechanism?
Authors: Julienne E. Bower, Patricia A. Ganz, Michael R. Irwin, Lorna Kwan, Elizabeth C. Breen, Steve W. Cole
Journal: Journal of Clinical Oncology (2011)

Fatigue, depression, and sleep disturbance are common adverse effects of cancer treatment and frequently co-occur. However, the possibility that inflammatory processes may underlie this constellation of symptoms has not been examined.Women (N = 103) who had recently finished primary treatment (ie, surgery, radiation, chemotherapy) for early-stage breast cancer completed self-report scales and provided blood samples for determination of plasma levels of inflammatory markers: soluble tumor necrosis factor (TNF) receptor II (sTNF-RII), interleukin-1 receptor antagonist, and C-reactive protein.Symptoms were elevated at the end of treatment; greater than 60% of participants reported clinically significant problems with fatigue and sleep, and 25% reported elevated depressive symptoms. Women treated with chemotherapy endorsed higher levels of all symptoms and also had higher plasma levels of sTNF-RII than women who did not receive chemotherapy (all P < .05). Fatigue was positively associated with sTNF-RII, particularly in the chemotherapy-treated group (P < .05). Depressive symptoms and sleep problems were correlated with fatigue but not with inflammatory markers.This study confirms high rates of behavioral symptoms in breast cancer survivors, particularly those treated with chemotherapy, and indicates a role for TNF-α signaling as a contributor to postchemotherapy fatigue. Results also suggest that fatigue, sleep disturbance, and depression may stem from distinct biologic processes in post-treatment survivors, with inflammatory signaling contributing relatively specifically to fatigue.
Atorvastatin Increases Plasma Soluble Fms-Like Tyrosine Kinase-1 and Decreases Vascular Endothelial Growth Factor and Placental Growth Factor in Association With Improvement of Ventricular Function in Acute Myocardial Infarction
Authors: Yasushi Kodama, Yoshinobu Kitta, Takamitsu Nakamura, Hajime Takano, Ken Umetani, Daisuke Fujioka, Yukio Saito, Ken-ichi Kawabata, Jyun-ei Obata, Akira Mende, Tsuyoshi Kobayashi, Kiyotaka Kugiyama
Journal: Journal of the American College of Cardiology (2006)
Early Insulin Use in Type 2 Diabetes
Authors: Jean-Louis Chiasson
Journal: Diabetes Care (2009)

It is generally recognized that type 2 diabetes is one of the major challenges of the 21st century. Its prevalence is growing rapidly worldwide, particularly in developing countries (1). It remains the first cause of blindness, end-stage renal disease, and nontraumatic lower-limb amputation and one of the major causes of cardiovascular disease (2,3). Because of its high morbidity and excess mortality, it has become a tremendous burden on health care cost (4).

In the last decade, a number of interventions have been shown to be effective in the prevention of diabetes in high-risk populations with impaired glucose tolerance and/or impaired fasting glucose (5–7). Yet, few countries have adopted policies for the screening and strategies for treating subjects with pre-diabetes. Furthermore, despite the development of newer therapies for treatment of diabetes, the disease is still associated with a high incidence of microangiopathy and macrovascular complications. Any new strategies that could help to curtail the burden of diabetes would be greatly appreciated.

More recently, it was postulated that early insulin replacement in type 2 diabetes, and perhaps even in pre-diabetes, may reduce cardiovascular risk and may even offer protection for the β-cell (8,9). However, a closer look at the available data does not support the hypothesis. The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) study is still ongoing and therefore does not allow any conclusion in pre-diabetes. In type 2 diabetes, however, the published data support neither a beneficial effect of insulin therapy per se on microvascular complications, nor on cardiovascular events and mortality. In addition, the data suggesting that insulin therapy can improve the β-cell response to a glucose challenge could just as well be interpreted as being due to the improvement in glycemic control, rather than to the insulin therapy. And finally, …
Curcumin Treatment Suppresses IKKβ Kinase Activity of Salivary Cells of Patients with Head and Neck Cancer: A Pilot Study
Authors: Suejung G. Kim, Mysore S. Veena, Saroj K. Basak, Eugene Han, Tracey Tajima, David W. Gjertson, Joshua Starr, Ofer Eidelman, Harvey B. Pollard, Meera Srivastava, Eri S. Srivatsan, Marilene B. Wang
Journal: Clinical Cancer Research (2011)

To determine whether curcumin would inhibit IκB kinase β (IKKβ) kinase activity and suppress expression of proinflammatory cytokines in head and neck squamous cell carcinoma cancer (HNSCC) patients.Saliva was collected before and after subjects chewed curcumin tablets. Protein was extracted and IKKβ kinase activity measured. Interleukin (IL)-6 and IL-8 levels in the salivary supernatants were measured by ELISA. IL-6, IL-8, and other interleukin were also measured independently with ELISA to confirm the inhibitory effect of curcumin on expression and secretion of salivary cytokines.Curcumin treatment led to a reduction in IKKβ kinase activity in the salivary cells of HNSCC patients (P < 0.05). Treatment of UM-SCC1 cells with curcumin as well as with post-curcumin salivary supernatant showed a reduction of IKKβ kinase activity. Significant reduction of IL-8 levels (P < 0.05) was seen in post-curcumin samples from patients with dental caries. Although there was reduced IL-8 expression in 8 of 21 post-curcumin samples of HNSCC patients, the data did not reach statistical significance. Saliva samples from HNSCC patients were also analyzed in a blinded fashion for expression of cytokines. IL-10, IFN-γ, IL-12p70, and IL-2 clustered together, and granulocyte macrophage colony stimulating factor and TNF-α clustered together. Log₁₀ ratio analysis showed decrease in expression of all nine cytokines in both the salivary supernatant and salivary cells of curcumin-treated samples.Curcumin inhibited IKKβ kinase activity in the saliva of HNSCC patients, and this inhibition correlated with reduced expression of a number of cytokines. IKKβ kinase could be a useful biomarker for detecting the effect of curcumin in head and neck cancer.
Tuberculous Pseudoaneurysm of the Descending Thoracic Aorta
Authors: D Sandron, P Patra, P Lelann, J Bouillard, D Pioche
Journal: JAMA (1963)

A tuberculous pseudo-aneurysm of the thoracic descending aorta was found in a 57 year-old female with haemoptysis three months after successful chemotherapy for a miliary tuberculosis. After aortic angiography, the aneurysm was resected and the aorta was repaired with a Dacron prosthetic graft. The patient is doing well one year after the operation.