tbuckley/cabot-search huggingface dataset:
Identifying Site-Specific Substitution Rates
Authors: S. Meyer
Journal: Molecular Biology and Evolution (2003)

A maximum likelihood framework for estimating site-specific substitution rates is presented that does not require any prior assumptions about the rate distribution. We show that, when the branching pattern of the underlying tree is known, the analysis of pairs of positions is sufficient to estimate site-specific rates. In the abscense of a known topology, we introduce an iterative procedure to estimate simultaneously the branching pattern, the branch lengths, and site-specific substitution rates. Simulations show that the evolutionary rate of fast-evolving sites can be reliably inferred and that the accuracy of rate estimates depends mainly on the number of sequences in the data set. Thus, large sets of aligned sequences are necessary for reliable site-specific rate estimates. The method is applied to the complete mitochondrial DNA sequence of 53 humans, providing a complete picture of the site-specific substitution rates in human mitochondrial DNA.
Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial
Authors: Robert J Motzer, Thomas E Hutson, Hilary Glen, M Dror Michaelson, Ana Molina, Timothy Eisen, Jacek Jassem, Jakub Zolnierek, Jose Pablo Maroto, Begoña Mellado, Bohuslav Melichar, Jiri Tomasek, Alton Kremer, Han-Joo Kim, Karen Wood, Corina Dutcus, James Larkin
Journal: The Lancet Oncology (2015)
Tissue Inhibitor of Metalloproteinase-3 via Oncolytic Herpesvirus Inhibits Tumor Growth and Vascular Progenitors
Authors: Yonatan Y. Mahller, Sachin S. Vaikunth, Maria C. Ripberger, William H. Baird, Yoshinaga Saeki, Jose A. Cancelas, Timothy M. Crombleholme, Timothy P. Cripe
Journal: Cancer Research (2008)

Abstract Malignant solid tumors remain a significant clinical challenge, necessitating innovative therapeutic approaches. Oncolytic viral therapy is a nonmutagenic, biological anticancer therapeutic shown to be effective against human cancer in early studies. Because matrix metalloproteinases (MMP) play important roles in the pathogenesis and progression of cancer, we sought to determine if “arming” an oncolytic herpes simplex virus (oHSV) with an MMP-antagonizing transgene would increase virus-mediated antitumor efficacy. We generated oHSVs that express human tissue inhibitor of metalloproteinases 3 (TIMP3) or firefly luciferase and designated them rQT3 and rQLuc, respectively. We evaluated the antitumor efficacy of these viruses against neuroblastoma and malignant peripheral nerve sheath tumor (MPNST) xenografts. Relative to rQLuc, rQT3-infected primary human MPNST and neuroblastoma cells exhibited equivalent virus replication but increased cytotoxicity and reduced MMP activity. In vivo, rQT3-treated tumors showed delayed tumor growth, increased peak levels of infectious virus, immature collagen extracellular matrix, and reduced tumor vascular density. Remarkably, rQT3 treatment reduced circulating endothelial progenitors, suggesting virus-mediated antivasculogenesis. We conclude that rQT3 enhanced antitumor efficacy through multiple mechanisms, including direct cytotoxicity, elevated virus titer, and reduced tumor neovascularization. These findings support the further development of combined TIMP-3 and oncolytic virotherapy for cancer. [Cancer Res 2008;68(4):1170–9]
BODE index and pulmonary rehabilitation in chronic respiratory failure
Authors: G. L. Biscione, L. Mugnaini, F. Pasqua, G. Crigna, L. Ferri, V. Cardaci, M. Fini, R. Gargano, P. Granone, A. Cesario
Journal: European Respiratory Journal (2006)

To the Editors: 

We read with interest the article by Cote and Celli 1 regarding the beneficial effects induced by pulmonary rehabilitation (PR) on the BODE (body mass index (BMI), degree of airway obstruction, dyspnoea, exercise capacity) index (BI) in patients with chronic obstructive pulmonary disease (COPD).

In an observational study, Cote and Celli 1 showed that the response to outpatient PR can be objectively measured using the BI, whose change provides information regarding ultimate survival, and that participation in a PR is associated with a decrease in the number of hospitalisations. This multidimensional 10-point scale has been previously shown to predict the death risk in COPD patients 2 …
Poor Glycemic Control Is an Independent Risk Factor for Low HDL Cholesterol in Patients With Type 2 Diabetes
Authors: Alessandra Gatti, Marianna Maranghi, Simonetta Bacci, Claudio Carallo, Agostino Gnasso, Elisabetta Mandosi, Mara Fallarino, Susanna Morano, Vincenzo Trischitta, Sebastiano Filetti
Journal: Diabetes Care (2009)

OBJECTIVE To determine whether the association observed between poor glycemic control and low HDL cholesterol in type 2 diabetes is dependent on obesity and/or hypertriglyceridemia. RESEARCH DESIGN AND METHODS We performed a cross-sectional study of 1,819 patients with type 2 diabetes and triglycerides &amp;lt;400 mg/dl enrolled at three diabetes centers in Italy. The risk for low HDL cholesterol was analyzed as a function of A1C levels. Odds ratios (ORs) were calculated after adjustment for confounding factors. RESULTS A 1% increase in A1C significantly increased the risk for low HDL cholesterol (OR 1.17 [95% CI 1.1–1.2], P = 0.00072); no changes were observed when age, sex, smoking, and lipid-lowering therapy were included in the model (1.17 [1.1–1.2], P = 0.00044). The association remained strong after adjustments for obesity and hypertriglyceridemia in multivariate analysis (1.12 [1.05–1.18], P = 0.00017). CONCLUSIONS Poor glycemic control appears to be an independent risk factor for low HDL cholesterol in type 2 diabetes.
Store-Independent Orai1/3 Channels Activated by Intracrine LeukotrieneC <sub>4</sub>
Authors: José C. González-Cobos, Xuexin Zhang, Wei Zhang, Brian Ruhle, Rajender K. Motiani, Rainer Schindl, Martin Muik, Amy M. Spinelli, Jonathan M. Bisaillon, Arti V. Shinde, Marc Fahrner, Harold A. Singer, Khalid Matrougui, Margarida Barroso, Christoph Romanin, Mohamed Trebak
Journal: Circulation Research (2013)

Through largely unknown mechanisms, Ca(2+) signaling plays important roles in vascular smooth muscle cell (VSMC) remodeling. Orai1-encoded store-operated Ca(2+) entry has recently emerged as an important player in VSMC remodeling. However, the role of the exclusively mammalian Orai3 protein in native VSMC Ca(2+) entry pathways, its upregulation during VSMC remodeling, and its contribution to neointima formation remain unknown.The goal of this study was to determine the agonist-evoked Ca(2+) entry pathway contributed by Orai3; Orai3 potential upregulation and role during neointima formation after balloon injury of rat carotid arteries.Ca(2+) imaging and patch-clamp recordings showed that although the platelet-derived growth factor activates the canonical Ca(2+) release-activated Ca(2+) channels via store depletion in VSMC, the pathophysiological agonist thrombin activates a distinct Ca(2+)-selective channel contributed by Orai1, Orai3, and stromal interacting molecule1 in the same cells. Unexpectedly, Ca(2+) store depletion is not required for activation of Orai1/3 channel by thrombin. Rather, the signal for Orai1/3 channel activation is cytosolic leukotrieneC4 produced downstream thrombin receptor stimulation through the catalytic activity of leukotrieneC4 synthase. Importantly, Orai3 is upregulated in an animal model of VSMC neointimal remodeling, and in vivo Orai3 knockdown inhibits neointima formation.These results demonstrate that distinct native Ca(2+)-selective Orai channels are activated by different agonists/pathways and uncover a mechanism whereby leukotrieneC4 acts through hitherto unknown intracrine mode to elicit store-independent Ca(2+) signaling that promotes vascular occlusive disease. Orai3 and Orai3-containing channels provide novel targets for control of VSMC remodeling during vascular injury or disease.
In memoriam Ann J. Woolcock. A star has been lost.
Authors: P. Macklem
Journal: European Respiratory Journal (2001)

A star has been lost. Ann Janet Woolcock died, too young, on February 17, 2001. The enduring friendship she and I shared has been a privilege that has enriched my life enormously. She was one of the few people whom I trusted absolutely. I miss her. She succumbed to a 15 year battle against breast cancer. For a long time almost nobody outside of her immediate family and her doctors knew about it. She insisted that it be kept a secret. She first felt the fatal breast lump in the fall of 1986 while she was at a meeting in Singapore. Because she needed to talk to someone and I was there, I knew from the very beginning and knew how much the news upset her. After returning to Australia she had a mastectomy, followed by chemotherapy because there were positive lymph nodes. There followed a period of relative quiescence when we all hoped that the dreaded disease had been conquered. Alas, in 1997, a lymph node biopsy showed a recurrence. Ann knew what the future held for her.

Rollo May has defined courage, not as the absence of fear, but as the ability to carry on in the face of despair. That fateful day in Singapore, I …
Safety and Efficacy of Stereotactic Body Radiotherapy for Stage I Non–Small-Cell Lung Cancer in Routine Clinical Practice: A Patterns-of-Care and Outcome Analysis
Authors: Matthias Guckenberger, Michael Allgäuer, Steffen Appold, Karin Dieckmann, Iris Ernst, Ute Ganswindt, Richard Holy, Ursula Nestle, Meinhard Nevinny-Stickel, Sabine Semrau, Florian Sterzing, Andrea Wittig, Nicolaus Andratschke
Journal: Journal of Thoracic Oncology (2013)
Detection of Hypokinesis by a Quantitative Analysis of Left Ventricular Cineangiograms
Authors: RICHARD F. LEIGHTON, SHARON M. WILT, RICHARD P. LEWIS
Journal: Circulation (1974)

A method for detecting left ventricular hypokinesis is proposed. It involves superimposition of left ventricular silhouettes traced from 30 degree right anterior oblique cineangiograms, correcting for thoracic cage motion, descent of the aortic valve and rotation of the apex. Normal values for the percent of systolic motion of seven endocardial segments have been established from measurements in 20 patients, permitting a statistical definition of hypokinesis. The use of this quantitative method has been compared with visual inspection of ventriculograms (qualitative method), resulting in differences in definition of hypokinetic segments by the two methods in 13 of 16 patients with coronary heart disease. When the quantitative method was used, only one hypokinetic segment was found which did not correspond to an obstructive coronary lesion while six such segments were defined using the qualitative method. In four patients segments thought to be hypokinetic (qualitative method) appeared to be akinetic (quantitative method). In six patients with cardiomyopathy, thought to have diffuse hypokinesis, all seven left ventricular segments were hypokinetic in only three patients. The use of a quantitative method appears to be essential to the proper interpretation of left ventricular wall motion and particularly to the detection of hypokinetic segments.
Pacing-induced heart failure: a model to study the mechanism of disease progression and novel therapy in heart failure
Authors: G Moe
Journal: Cardiovascular Research (1999)

Time for primary review 29 days. 

Congestive heart failure (CHF) is a common clinical problem that confronts physicians and is often the final manifestation of many cardiovascular disorders. The diagnosis of CHF is accompanied by significant mortality and morbidity [1]. The syndrome is characterized by a relentless progressive course that is often manifested as repeated hospital admissions imposing heavy economic burden on the health care delivery system [2,3]. Therefore, basic research into the fundamental mechanisms accounting for the progression of CHF with the hope for developing novel therapeutic approaches to alter the progressive course has become a priority for many researchers. To facilitate these investigations, an animal model that closely mimics human CHF and also exhibits key components of what are now perceived to be important pathogenetic contributors to CHF progression is ideal. It is therefore the objective of this review to highlight how the model of pacing-induced cardiomyopathy has provided insights into the mechanisms of progression of CHF.

Clinicians have traditionally viewed CHF as being predominantly a haemodynamic disorder. Accordingly, haemodynamic descriptors such as elevated cardiac filling pressures, pulmonary venous and arterial hypertension, reduced cardiac output, and elevated systemic and pulmonary vascular resistance were used to characterize patients with CHF. While the haemodynamic descriptors can account for some of the clinical manifestations of CHF, such as dyspnea, fatigue and fluid retention, they do not adequately address the invariably progressive nature of the condition. In recent years, it has become apparent that CHF is a syndrome associated with a complex array of perturbations at multiple levels starting from the subcellular to the whole organ level. These alterations include profound structural and functional changes, which may culminate in the death of myocytes as well as major disruption of the cardiac extracellular matrix [4]. Both of these processes may … 

* Corresponding author.
MB-37 * METACHRONOUS SUPRATENTORIAL INTRACRANIAL MALIGNANT TUMORS IN TWO PEDIATRIC PATIENTS WITH INFRATENTORIAL MEDULLOBLASTOMA ON HORMONE THERAPY
Authors: A. Perez, J. Shiflett, B. Herrington
Journal: Neuro-Oncology (2015)

INTRODUCTION: Medulloblastomas are classified by the WHO as embryonal tumors and comprise the most common of the malignant pediatric brain tumors while accounting for twenty percent of all pediatric brain tumors. The phenomenon of second malignancy is uncommonly seen in cases of uniform histology and are more rare when they are of a different histological type. The authors report two cases of infratentorial medulloblastomas that subsequently developed a grade IV glioma in one case, and a second medulloblastoma in the other. PRESENTATION: An eleven year-old female had been experiencing vision difficulty with right eye deviation and emesis. MRI showed a partially-enhancing posterior fossa mass lesion. Four years later, she was discovered to have a right parietal ring-enhancing lesion on routine surveillance. A four year-old female presented to our institution with a one-month history of headaches and emesis and a posterior fossa mass lesion. Three and a half years later, subsequent routine surveillance revealed a new enhancing lesion of the left temporal region with a higher Ki-67 labeling index. TREATMENT: Our first patient underwent sub-occipital craniotomy and gross-total resection for her medulloblatoma followed by chemoradiation under a COG protocol consisting of Vincristine, Cisplatin, and Cyclophosphamide and 23.4 Gy with a posterior fossa boost of 30.6 Gy. She underwent craniotomy for the GBM with GTR followed by maintenance chemotherapy. Our second patient underwent similar therapy with GTR for both lesions then was initiated after the second resection on a COG trial consisting of Bevacizumab, Temodar, and Irinotecan. Of note, both patients were on hormone therapy: GH and Lupron. CONCLUSIONS: We report two cases of infratentorial medulloblastoma with subsequent development of supratentorial lesions with discrepant histological profiles. A second malignancy of different cellular origin is rare, and molecular profiling of the two metachronous medulloblastomas will reveal whether they represent unique entities.
Update in Cystic Fibrosis 2008
Authors: Felix Ratjen
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, and more than 1,500 distinct mutations with different functional consequences have been reported in the CFTR database (1). Multiple organs are involved in the disease process, but lung disease continues to account for the majority of morbidity and mortality in patients with CF. Knowledge about the pathophysiology of cystic fibrosis has greatly increased in recent years and CF has evolved into a model demonstrating how a better understanding of the underlying defect can lead to novel therapeutic approaches. However, complex interactions exist between CFTR and other regulatory proteins and all of the relevant components that cause disease manifestations both in the lung and in other organ systems are still incompletely understood. A large body of evidence supports the concept that airway surface liquid depletion is a key component in the development of CF lung disease. This is thought to be the consequence of an imbalance in defective chloride secretion and enhanced sodium absorption that has been consistently observed in studies of CF epithelium. The net fluid loss on the airway surface leads to the collapse of cilia and impaired mucociliary transport. However, regulation of mucociliary clearance is a dynamic process involving other epithelial channels that are thought to play an important role in stress-induced increases in airway surface liquid (ASL) height (2). These CFTR independent pathways are functional in CF and can be up-regulated by both external and internal stimuli, such as ATP, which may explain why mucociliary clearance is reduced but not absent in patients with CF (2). Improving airway surface hydration either with pharmacological agents or osmotic agents, such as hypertonic saline, has become an important therapeutic target in CF (3, 4).
Gadolinium-Enhanced 3-Dimensional Magnetic Resonance Angiography of Pulmonary Blood Supply in Patients With Complex Pulmonary Stenosis or Atresia
Authors: Tal Geva, Gerald F. Greil, Audrey C. Marshall, Michael Landzberg, Andrew J. Powell
Journal: Circulation (2002)

Background — In patients with complex pulmonary stenosis or atresia, a detailed delineation of all sources of pulmonary blood supply is necessary for planning surgical and transcatheter procedures and usually requires diagnostic cardiac catheterization. The goals of this study were to determine whether gadolinium-enhanced 3D magnetic resonance angiography (MRA) can provide a noninvasive alternative to diagnostic catheterization and to compare MRA and x-ray angiography measurements of pulmonary arteries and aortopulmonary collaterals (APCs). Methods and Results — Thirty-two patients with pulmonary stenosis or atresia (median age: 4.7 years, range: 1 day to 46.9 years) underwent both MRA and cardiac catheterization (median time: 1 month). Diagnoses included tetralogy of Fallot (TOF) with pulmonary atresia (n=13), TOF with pulmonary stenosis (n=4), post-Fontan palliation (n=5), and other complex congenital heart disease (n=10). Compared with catheterization and surgical observations, MRA had a 100% sensitivity and specificity for the diagnosis of main (n=10) and branch pulmonary artery (PA) stenosis or hypoplasia (n=38), as well as absent (n=5) or discontinuous (n=4) branch PAs. All 48 major APCs diagnosed by catheterization were correctly diagnosed by MRA. Three additional APCs were diagnosed by MRA but not by catheterization. The mean difference between MRA and catheterization measurements of 33 pulmonary vessel diameters was 0.5±1.5 mm, with a mean interobserver difference of 0.4±1.5 mm. Conclusions — Gadolinium-enhanced 3D MRA is a fast and accurate technique for delineation of all sources of pulmonary blood supply in patients with complex pulmonary stenosis and atresia and can be considered a noninvasive alternative to diagnostic catheterization with x-ray angiography.
Pore-forming bacterial toxins potently induce release of nitric oxide in porcine endothelial cells.
Authors: N Suttorp, M Fuhrmann, S Tannert-Otto, F Grimminger, S Bhadki
Journal: The Journal of Experimental Medicine (1993)

Nitric oxide (NO) is believed to play an important role in sepsis-related hypotension. We examined the effects of two pore-forming bacterial exotoxins, Escherichia coli hemolysin and Staphylococcus aureus alpha-toxin, on NO formation in cultured porcine pulmonary artery endothelial cells. NO was quantified using a difference-spectrophotometric method based on the rapid and stoichiometric reaction of NO with oxyhemoglobin. Endothelial cyclic guanosine monophosphate levels were also monitored. Both exotoxins increased NO synthesis in endothelial cells in a time- and dose-dependent manner to an extent exceeding that observed with the ionophore A23187 or thrombin. The capacity of exotoxins to induce NO formation may be relevant in patients with severe local or systemic bacterial infections.
Extra-Articular Tenodesis for Anterior Cruciate Deficient Knees: A Review of the Ellison Repair
Authors: R A Marston, S C Chen
Journal: Journal of the Royal Society of Medicine (1993)

Twenty-two patients who underwent an Ellison extra-articular tenodesis for anterolateral instability of the knee, performed by one surgeon (SCC), have been reviewed after a mean follow-up of 59 months. Seventy-seven per cent had a good or excellent result enabling them to return to their pre-injury level of sport. These results compare very favourably with intra-articular repair but are not associated with such severe complications.
<i>In vitro</i> studies of degradation of birch and timothy pollen allergen preparations by human duodenal juice
Authors: R. Einarsson, B. Renck, E. Taudorf
Journal: Allergy (1988)

The hydrolysis of birch and timothy pollen allergen preparations by duodenal juice from an adult volunteer was studied in vitro with the aid of rocket immunoelectrophoresis, radiorocket immunoelectrophoresis and RAST-inhibition. The results achieved with all methods were similar. The duodenal juice had the capacity to hydrolyse both the grass and tree pollen proteins, and after 30 min preincubation only 10% of the original birch and timothy allergenic activity remained. Heat treatment of the duodenal juice completely destroyed the proteolytic activity (i.e. no hydrolysis occurred) while protease inhibitors only marginally prevented the hydrolysis.
Are two really always better than one? Results, concerns and controversies in the use of bilateral internal thoracic arteries for coronary artery bypass grafting in the elderly: A systematic review and meta-analysis
Authors: Salil V. Deo, Salah E. Altarabsheh, Ishan K. Shah, Yang Hyun Cho, Michael McGraw, Basar Sarayyepoglu, Benjamin Medalion, Alan H. Markowitz, Soon J. Park
Journal: International Journal of Surgery (2015)
The Broken Column
Authors: D. O'Neill
Journal: BMJ (2011)

It is a sad reality that pain, one of the most common and distressing symptoms of illness, is all too often neglected by doctors and nurses. Detection and measurement of pain in our patients is often shockingly deficient and unsystematic, and the problem is compounded by routine undertreatment.

How can it be that large groups of generally well intentioned, educated, and motivated people are insensitive to this aspect of their vocation? Among the possible explanations is, of course, that pain, unlike broken bones or cancerous masses, is invisible. In addition, the mean age of healthcare workers is considerably lower than that …