tbuckley/cabot-search huggingface dataset:
Atrial reentry around an anatomic barrier with a partially refractory excitable gap. A canine model of atrial flutter.
Authors: L H Frame, R L Page, B F Hoffman
Journal: Circulation Research (1986)

We have characterized, in dogs, a model of inducible regular atrial tachycardia that resembles atrial flutter. The model involves creating a Y-shaped lesion comprised of an intercaval incision and a connected incision across the right atrium. It is suitable for serial studies of the effects of pacing or antiarrhythmic drugs in chronically instrumented animals studied in the awake state for at least several months. The postoperative cycle length of the induced tachycardia varies from 143 to 188 msec, depending on the size of the dog. The tachycardia cycle length was consistent for each dog, and the rhythm--once induced--was very stable until terminated by pacing. The mechanism of the tachycardia was reentry due to circus movement based on the ability to induce and terminate it by premature impulses or overdrive, the ability to reset the tachycardia by single premature stimuli, the pattern of entrainment during overdrive stimulation, and the ability to terminate the tachycardia by interrupting the conduction pathway. The window of reset determined by the range of coupling intervals of premature stimuli that were able to enter and reset the tachycardia ranged from 56 to 82 msec. There appears to be incomplete recovery of excitability by the end of the excitable gap as evidenced by the fact that even late premature impulses that enter the reentrant circuit conduct more slowly than the tachycardia impulse, and because stimulation of muscarinic receptors that shortens the duration of the action potential and refractoriness also reduces the cycle length of the tachycardia. Epicardial and endocardial activation mapping during tachycardia showed the reentrant pathway does not merely encircle the lesion, particularly over the left atrial epicardium near the intercaval lesion. Rather, the impulse appears to travel around the atrial tissue just above the tricuspid ring, including a portion that travels through the right side of the lower intraatrial septum. Thus, the model involves circus movement around an anatomic barrier through normal tissue that contains no depressed segments. During the circus movement, there is a relatively long excitable gap during which there is incomplete recovery of excitability. This model should be useful for studies of the mechanism of antiarrhythmic drug action and the responses to premature stimulation in this particular subclass of reentrant rhythms, and for comparison with the behavior and responses of other forms of reentry.
Epigenetic Inactivation Implies Independent Functions for Insulin-like Growth Factor Binding Protein (IGFBP)-Related Protein 1 and the Related IGFBPL1 in Inhibiting Breast Cancer Phenotypes
Authors: Paul Smith, Linda J. Nicholson, Nelofer Syed, Annette Payne, Louise Hiller, Ornella Garrone, Marcella Occelli, Milena Gasco, Tim Crook
Journal: Clinical Cancer Research (2007)

Abstract Purpose: To analyze epigenetic regulation of two related genes, insulin-like growth factor binding protein-related protein 1 (IGFBP-rP1) and IGFBPL1, and its significance as a determinant of clinical phenotypes in human breast cancer. Experimental Design: We have investigated the expression and epigenetic regulation of IGFBP-rP1 and IGFBPL1 in human breast cancer cell lines and primary and metastatic carcinomas. Results: Expression of IGFBP-rP1 and IGFBPL1 is down-regulated in breast cancer cell lines. Aberrant methylation in the CpG islands of each gene correlates well with loss of expression at the mRNA level. Analysis of methylation in DNA isolated from human primary breast tumors showed that methylation in either gene was associated with a worse overall survival (OS; P = 0.008) and disease-free survival (DFS) following surgery (P = 0.04) and worse DFS following adjuvant chemotherapy (P = 0.01). Methylation of IGFBP-rP1 alone was associated with a trend toward decreased OS (P = 0.10) and decreased DFS (P = 0.25). Methylation in IGFBPL1 was clearly associated with worse OS (P = 0.001) and DFS (P &amp;lt; 0.0001). Methylation in either IGFBP-rP1 or IGFBPL1 was significantly associated with nodal disease (P &amp;lt; 0.001). Conclusions: Expression of IGFBP-rP1 and IGFBPL1 is regulated by aberrant hypermethylation in breast cancer, implying that inactivation of these genes is involved in the pathogenesis of this malignancy. Analysis of methylation of these genes may have utility in prediction of clinical phenotypes, such as nodal disease and response to chemotherapy.
Multimodal Mass Spectrometric Imaging of Small Molecules Reveals Distinct Spatio-Molecular Signatures in Differentially Metastatic Breast Tumor Models
Authors: Erika R. Amstalden van Hove, Tiffany R. Blackwell, Ivo Klinkert, Gert B. Eijkel, Ron M.A. Heeren, Kristine Glunde
Journal: Cancer Research (2010)

Phosphocholine (PC) and total choline (tCho) are increased in malignant breast tumors. In this study, we combined magnetic resonance spectroscopic imaging (MRSI), mass spectrometry (MS) imaging, and pathologic assessment of corresponding tumor sections to investigate the localization of choline metabolites and cations in viable versus necrotic tumor regions in the nonmetastatic MCF-7 and the highly metastatic MDA-MB-231 breast cancer xenograft models. In vivo three-dimensional MRSI showed that high tCho levels, consisting of free choline (Cho), PC, and glycerophosphocholine (GPC), displayed a heterogeneous spatial distribution in the tumor. MS imaging performed on tumor sections detected the spatial distributions of individual PC, Cho, and GPC, as well as sodium (Na+) and potassium (K+), among many others. PC and Cho intensity were increased in viable compared with necrotic regions of MDA-MB-231 tumors, but relatively homogeneously distributed in MCF-7 tumors. Such behavior may be related to the role of PC and PC-related enzymes, such as choline kinase, choline transporters, and others, in malignant tumor growth. Na+ and K+ colocalized in the necrotic tumor areas of MDA-MB-231 tumors, whereas in MCF-7 tumors, Na+ was detected in necrotic and K+ in viable tumor regions. This may be attributed to differential Na+/K+ pump functions and K+ channel expressions. Principal component analysis of the MS imaging data clearly identified different tumor microenvironmental regions by their distinct molecular signatures. This molecular information allowed us to differentiate between distinct tumor regions and tumor types, which may, in the future, prove clinically useful in the pathologic assessment of breast cancers.
Graphene Oxide‐Based Antibacterial Cotton Fabrics
Authors: Jinming Zhao, Bo Deng, Min Lv, Jingye Li, Yujie Zhang, Haiqing Jiang, Cheng Peng, Jiang Li, Jiye Shi, Qing Huang, Chunhai Fan
Journal: Advanced Healthcare Materials (2013)

Graphene oxide (GO) is an excellent bacteria-killing nanomaterial. In this work, macroscopic applications of this promising nanomaterial by fixing GO sheets onto cotton fabrics, which possess strong antibacterial property and great laundering durability, are reported. The GO-based antibacterial cotton fabrics are prepared in three ways: direct adsorption, radiation-induced crosslinking, and chemical crosslinking. Antibacterial tests show that all these GO-containing fabrics possess strong antibacterial property and could inactivate 98% of bacteria. Most significantly, these fabrics can still kill >90% bacteria even after being washed for 100 times. Also importantly, animal tests show that GO-modified cotton fabrics cause no irritation to rabbit skin. Hence, it is believed that these flexible, foldable, and re-usable GO-based antibacterial cotton fabrics have high promise as a type of new nano-engineered antibacterial materials for a wide range of applications.
Utility of Absolute and Relative Changes in Cardiac Troponin Concentrations in the Early Diagnosis of Acute Myocardial Infarction
Authors: Tobias Reichlin, Affan Irfan, Raphael Twerenbold, Miriam Reiter, Willibald Hochholzer, Hanna Burkhalter, Stefano Bassetti, Stephan Steuer, Katrin Winkler, Federico Peter, Julia Meissner, Philip Haaf, Mihael Potocki, Beatrice Drexler, Stefan Osswald, Christian Mueller
Journal: Circulation (2011)

Background— Current guidelines for the diagnosis of acute myocardial infarction (AMI), among other criteria, also require a rise and/or fall in cardiac troponin (cTn) levels. It is unknown whether absolute or relative changes in cTn have higher diagnostic accuracy and should therefore be preferred. Methods and Results— In a prospective, observational, multicenter study, we analyzed the diagnostic accuracy of absolute (Δ) and relative (Δ%) changes in cTn in 836 patients presenting to the emergency department with symptoms suggestive of AMI. Blood samples for the determination of high-sensitive cTn T and cTn I ultra were collected at presentation and after 1 and 2 hours in a blinded fashion. The final diagnosis was adjudicated by 2 independent cardiologists. The area under the receiver operating characteristic curve for diagnosing AMI was significantly higher for 2-hour absolute (Δ) versus 2-hour relative (Δ%) cTn changes (area under the receiver operating characteristic curve [95% confidence interval], high-sensitivity cTn T: 0.95 [0.92 to 0.98] versus 0.76 [0.70 to 0.83], P &lt;0.001; cTn I ultra: 0.95 [0.91 to 0.99] versus 0.72 [0.66 to 0.79], P &lt;0.001). The receiver operating characteristic curve–derived cutoff value for 2-hour absolute (Δ) change was 0.007 μg/L for high-sensitivity cTn T and 0.020 μg/L for cTn I ultra (both cutoff levels are half of the 99th percentile of the respective cTn assay). Absolute changes were superior to relative changes in patients with both low and elevated baseline cTn levels. Conclusions— Absolute changes of cTn levels have a significantly higher diagnostic accuracy for AMI than relative changes, and seem therefore to be the preferred criteria to distinguish AMI from other causes of cTn elevations. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00470587.
Oncogenic EGFR Signaling Activates an mTORC2–NF-κB Pathway That Promotes Chemotherapy Resistance
Authors: Kazuhiro Tanaka, Ivan Babic, David Nathanson, David Akhavan, Deliang Guo, Beatrice Gini, Julie Dang, Shaojun Zhu, Huijun Yang, Jason De Jesus, Ali Nael Amzajerdi, Yinan Zhang, Christian C. Dibble, Hancai Dan, Amanda Rinkenbaugh, William H. Yong, Harry V. Vinters, Joseph F. Gera, Webster K. Cavenee, Timothy F. Cloughesy, Brendan D. Manning, Albert S. Baldwin, Paul S. Mischel
Journal: Cancer Discovery (2011)

Although it is known that mTOR complex 2 (mTORC2) functions upstream of Akt, the role of this protein kinase complex in cancer is not well understood. Through an integrated analysis of cell lines, in vivo models, and clinical samples, we demonstrate that mTORC2 is frequently activated in glioblastoma (GBM), the most common malignant primary brain tumor of adults. We show that the common activating epidermal growth factor receptor (EGFR) mutation (EGFRvIII) stimulates mTORC2 kinase activity, which is partially suppressed by PTEN. mTORC2 signaling promotes GBM growth and survival and activates NF-κB. Importantly, this mTORC2-NF-κB pathway renders GBM cells and tumors resistant to chemotherapy in a manner independent of Akt. These results highlight the critical role of mTORC2 in the pathogenesis of GBM, including through the activation of NF-κB downstream of mutant EGFR, leading to a previously unrecognized function in cancer chemotherapy resistance. These findings suggest that therapeutic strategies targeting mTORC2, alone or in combination with chemotherapy, will be effective in the treatment of cancer.This study demonstrates that EGFRvIII-activated mTORC2 signaling promotes GBM proliferation, survival, and chemotherapy resistance through Akt-independent activation of NF-κB. These results highlight the role of mTORC2 as an integrator of two canonical signaling networks that are commonly altered in cancer, EGFR/phosphoinositide-3 kinase (PI3K) and NF-κB. These results also validate the importance of mTORC2 as a cancer target and provide new insights into its role in mediating chemotherapy resistance, suggesting new treatment strategies.
Associations between metabolic dysregulation and circulating biomarkers of fibrosis: the Cardiovascular Health Study
Authors: Isha Agarwal, Nicole L. Glazer, Eddy Barasch, Luc Djousse, John S. Gottdiener, Joachim H. Ix, Jorge R. Kizer, Eric B. Rimm, David S. Siscovick, George L. King, Ken J. Mukamal
Journal: Metabolism (2015)
The Unequal World of Health Data
Authors: Peter Byass
Journal: PLoS Medicine (2009)

Health data are a slippery commodity.It is not difficult to reach subjective agreement that such data are unequally distributed around the world, both in terms of quantity and quality.But objective assessments are more difficult, since they need to be based on data-and the data about the data may themselves be problematic or incomplete.Perhaps not surprisingly, therefore, literature is relatively scarce on the extent and quality of primary sources of health data on a global scale, even though there are many reports that present aggregated global data on various health issues [1,2], sometimes giving the impression that those estimates carry a high degree of certainty.
A Biochemical Study of Spontaneous Atherosclerosis in Pigeons
Authors: HUGH B. LOFLAND, THOMAS B. CLARKSON
Journal: Circulation Research (1959)

Two breeds of pigeons (White Carneau and Silver King) have been found to have a high incidence of spontaneous atheromatous lesions in the aorta, while two breeds of homing pigeons (Racing Homers and Show Racers) seemed to be resistant to atherosclerosis. The weight of the aorta, and its cholesterol content, paralleled the severity of the disease. The levels of serum cholesterol and phospholipids, and the cholesterol: phospholipid ratio, however, appear to be unrelated to the incidence and severity of atherosclerosis in pigeons. The differences observed among the four breeds of birds showed little correlation with age, sex, diet, or physical activity.
Oxygen-Sensitive Kv Channel Gene Transfer Confers Oxygen Responsiveness to Preterm Rabbit and Remodeled Human Ductus Arteriosus
Authors: Bernard Thébaud, Evangelos D. Michelakis, Xi-Chen Wu, Rohit Moudgil, Michael Kuzyk, Jason R.B. Dyck, Gwyneth Harry, Kyoko Hashimoto, Alois Haromy, Ivan Rebeyka, Stephen L. Archer
Journal: Circulation (2004)

Oxygen (O2)-sensitive K+ channels mediate acute O2 sensing in many tissues. At birth, initial functional closure of the ductus arteriosus (DA) results from O2-induced vasoconstriction. This mechanism often fails in premature infants, resulting in persistent DA, a common form of congenital heart disease. We hypothesized that the basis for impaired O2 constriction in preterm DA is reduced expression and function of O2-sensitive, voltage-gated (Kv) channels.Preterm rabbit DA rings have reduced O2 constriction (even after inhibition of prostaglandin and nitric oxide synthases), and preterm DA smooth muscle cells (DASMCs) display reduced O2-sensitive K+ current. This is associated with decreased mRNA and protein expression of certain O2-sensitive Kv channels (Kv1.5 and Kv2.1) but equivalent expression of the L-type calcium channel. Transmural Kv1.5 or Kv2.1 gene transfer "rescues" the developmental deficiency, conferring O2 responsiveness to preterm rabbit DAs. Targeted SMC Kv1.5 gene transfer also enhances O2 constriction in human DAs.These data demonstrate a central role for developmentally regulated DASMC O2-sensitive Kv channels in the functional closure of the DA. Modulation of Kv channels may have therapeutic potential in diseases associated with impaired O2 responsiveness, including persistent DA.
BLOOD GROUP ACTIVITY OF GRAM-NEGATIVE BACTERIA
Authors: Georg F. Springer, Peter Williamson, William C. Brandes
Journal: The Journal of Experimental Medicine (1961)

Distribution of blood group A, B, and H(O) activities among 282 aerobic Gram-negative bacteria, many isolated from the blood of patients, has been studied. Almost half of these bacteria were found to be blood group active. About 10 per cent of the organisms exhibited high, disproportional activities, which in some instances approached those of crude human blood group mucoids. No significant, specific D (Rho), M, or N activity was found in approximately 70 members of the Enterobacteriaceae. An attempt was made to correlate the observed activity of a given organism of known O somatic antigen with its monosaccharide components. The presence of those sugars which account for the specificity of human blood group mucoids was noted. The bearing of these findings on the origin of human anti-A and anti-B isoantibodies has been mentioned.
Genetic Analysis of Cancer-Implicated MicroRNA in Ovarian Cancer
Authors: Jennifer L. Bearfoot, David Y.H. Choong, Kylie L. Gorringe, Ian G. Campbell
Journal: Clinical Cancer Research (2008)

Abstract Purpose: There is accumulating evidence that microRNAs may function like classic tumor suppressor genes but little is known about their mechanism of inactivation in cancer cells. We investigated whether somatic mutations are a common mechanism of inactivation of microRNA genes in ovarian cancer. Experimental Design: Ten cancer-implicated microRNA genes were analyzed for somatic mutations in 90 ovarian epithelial cancers and matching normal DNA. High-resolution melt analysis and bidirectional sequencing was used to detect sequence variations. Results: High-resolution melt analysis and direct sequencing did not identify any somatic mutations but did reveal numerous novel and previously reported germ line base substitutions, deletions, and insertions surrounding the mature microRNA sequences. The majority of variants were detected in the same proportion of non–cancer control individuals suggesting that they do not represent ovarian cancer–predisposing alleles. Conclusion: The absence of somatic mutations in any of the 10 cancer-implicated microRNAs in our large cohort of ovarian tumors suggests that this may be an uncommon mechanism of inactivation of microRNAs in ovarian cancer.
Evolution of pulmonary inflammation and nutritional status in infants and young children with cystic fibrosis
Authors: S. C. Ranganathan, F. Parsons, C. Gangell, S. Brennan, S. M. Stick, P. D. Sly
Journal: Thorax (2011)

<h3>Introduction</h3> Improved nutrition is the major proven benefit of newborn screening programmes for cystic fibrosis (CF) and is associated with better clinical outcomes. It was hypothesised that early pulmonary inflammation and infection in infants with CF is associated with worse nutrition. <h3>Methods</h3> Weight, height and pulmonary inflammation and infection in bronchoalveolar lavage (BAL) were assessed shortly after diagnosis in infants with CF and again at 1, 2 and 3 years of age. Body mass index (BMI) was expressed as z-scores. Inflammatory cells and cytokines (interleukin 1β (IL-1β), IL-6, IL-8 and tumour necrosis factor α (TNFα)), free neutrophil elastase activity and myeloperoxidase were measured in BAL. Mixed effects modelling was used to assess longitudinal associations between pulmonary inflammation, pulmonary infection (<i>Staphylococcus aureus</i> and <i>Pseudomonas</i><i>aeruginosa</i>) and BMI z-score after adjusting for potential confounding factors. <h3>Results</h3> Forty-two infants were studied (16 (38%) male; 39 (93%) pancreatic insufficient); 36 were diagnosed by newborn screening (at median age 4 weeks) and six by early clinical diagnosis (meconium ileus). Thirty-one (74%) received antistaphylococcal antibiotics. More than two-thirds were asymptomatic at each assessment. Mean BMI z-scores were −1.5 at diagnosis and 0.5, −0.2 and −0.1 at 1, 2 and 3 years, respectively. Neutrophil elastase and infection with <i>S</i><i>aureus</i> were associated with lower BMI, whereas age (p=0.01) and antistaphylococcal antibiotics (p=0.013) were associated with increased BMI. On average, each log<sub>10</sub> increase in free neutrophil elastase activity was associated with a 0.43 (95% CI 0.06 to 0.79) reduction in BMI z-score. <h3>Discussion</h3> Early nutritional status is associated with the underlying pulmonary pathophysiology in CF, and better understanding of these relationships is required. Studies are required to assess whether interventions can decrease pulmonary inflammation and improve nutrition. Early surveillance will enable such targeted interventions with the aim of improving these important clinical outcomes.
A stable form of delayed-type hypersensitivity.
Authors: P H Lagrange, G B Mackaness
Journal: The Journal of Experimental Medicine (1975)

An antigen dose below the level needed to provoke an antibody response produces in mice a persistent, but minor degree of delayed-type hypersensitivity (dth) to sheep red blood cells. The DTH is unstable. It is erased by larger doses of antigen and cannot be built upon by further antigenic stimulation. The much higher levels of DTH resulting from immunization under the modulating influence of cyclophosphamide (CY) or BCG persist under strong secondary antigenic stimulation, though the former is subject to partial suppression unless CY is used to prevent the secondary humoral response. The DTH produced by a BCG-modulated primary response is not subject to this suppressive effect of a secondary antibody response. In this case the anamnestic T-cell response is very brisk and cannont be potentiated by giving CY at the time of the secondary antigenic stimulus. This effect is not due to the modulating influence of a residual BCG infection. It results from a permanent change induced during the primary response. The mediator cells formed under the influence of BCG are apparently resistant to inhibition by blocking serum containing immune complexes. Even the actively dividing T cells which are susceptible to vinblastine, and most readily blocked in the absence of BCG, are highly resistant to blocking by immune complexes. It is not clear whether these cells are intrinsically different or whether their insensitivity to blocking results from features peculiar to the humoral response that accompanies a BCG-modulated primary response. The mediator cells produced by both BCG- and CY-modulated responses become vinblastine resistant, relatively insensitive to humoral blocking factors, and capable of surviving in a functionally active form in syngeneic recipients with an apparent half-life of about 50 days. There were indications, however, that their effective life-span may be greatly extended in some circumstances by persisting antigenic stimulation; and in the case of BCG-modulated immunity the prevailing level of T-cell activity can be greatly augmented by a further antigenic stimulus without the necessity for renewed exposure to BCG.