tbuckley/cabot-search huggingface dataset:
Interstitial Flow in a 3D Microenvironment Increases Glioma Invasion by a CXCR4-Dependent Mechanism
Authors: Jennifer M. Munson, Ravi V. Bellamkonda, Melody A. Swartz
Journal: Cancer Research (2012)

Abstract Brain tumor invasion leads to recurrence and resistance to treatment. Glioma cells invade in distinct patterns, possibly determined by microenvironmental cues including chemokines, structural heterogeneity, and fluid flow. We hypothesized that flow originating from pressure differentials between the brain and tumor is active in glioma invasion. Using in vitro models, we show that interstitial flow promotes cell invasion in multiple glioma cell lines. Flow effects were CXCR4-dependent, because they were abrogated by CXCR4 inhibition. Furthermore, CXCR4 was activated in response to flow, which could be responsible for enhanced cell motility. Flow was seen to enhance cell polarization in the flow direction, and this flow-induced polarization could be blocked by CXCR4 inhibition or CXCL12 oversaturation in the matrix. Furthermore, using live imaging techniques in a three-dimensional flow chamber, there were more cells migrating and more cells migrating in the direction of flow. This study shows that interstitial flow is an active regulator of glioma invasion. The new mechanisms of glioma invasion that we identify here—namely, interstitial flow-enhanced motility, activation of CXCR4, and CXCL12-driven autologous chemotaxis—are significant in therapy to prevent or treat brain cancer invasion. Current treatment strategies can lead to edema and altered flow in the brain, and one popular experimental treatment in clinical trials, convection enhanced delivery, involves enhancement of flow in and around the tumor. A better understanding of how interstitial flow at the tumor margin can alter chemokine distributions, cell motility, and directed invasion offers a better understanding of treatment failure. Cancer Res; 73(5); 1536–46. ©2012 AACR.
Proximity to coke works and hospital admissions for respiratory and cardiovascular disease in England and Wales
Authors: P Aylin
Journal: Thorax (2001)

<h3>BACKGROUND</h3> The incidence of hospital admissions for respiratory and cardiovascular diseases in areas close to operating coke works in England and Wales was investigated. <h3>METHODS</h3> A small area study using distance from source as a proxy for exposure was undertaken in subjects aged 65 or over and children under 5 years within 7.5 km of four coke works (1991 estimated populations 87 760 and 43 932, respectively). The main outcome measures were emergency hospital admissions in 1992/3–1994/5 with a primary diagnosis of coronary heart disease (ICD 410–414), stroke (ICD 431–438), all respiratory diseases (ICD 460–519), chronic obstructive pulmonary disease (ICD 491–492), and asthma (ICD 493) in those aged 65 or over, and all respiratory and asthma admissions in children under 5 years of age. <h3>RESULTS</h3> At age 65 or over the combined estimate of relative risk with proximity to coke works (per km) ranged from 0.99 (95% CI 0.90 to 1.09) for chronic obstructive pulmonary disease to 1.03 (95% CI 0.94 to 1.13) for asthma. For children under 5 years the combined estimate of risk was 1.08 (95% CI 0.98 to 1.20) for all respiratory disease and 1.07 (95% CI 0.98 to 1.18) for asthma. There was evidence of significant heterogeneity in risk estimates between coke work groups, especially in children under 5 years (p&lt;0.001 and p=0.004 for respiratory disease and asthma, respectively). For the Teesside coke works in North East England the relative risk with proximity (per km) was 1.09 (95% CI 1.06 to 1.12) for respiratory disease and 1.09 (95% CI 1.04 to 1.15) for asthma. <h3>CONCLUSIONS</h3> No evidence overall was found for an association between hospital admissions and living near operational coke works in England and Wales. Trends of a higher risk of hospital admission for respiratory disease and asthma among children with proximity to the Teesside plant require further investigation.
Lymphoid tissue inducer–like cells are an innate source of IL-17 and IL-22
Authors: Hiroaki Takatori, Yuka Kanno, Wendy T. Watford, Cristina M. Tato, Greta Weiss, Ivaylo I. Ivanov, Dan R. Littman, John J. O'Shea
Journal: The Journal of Experimental Medicine (2008)

The interleukin (IL) 17 family of cytokines has emerged to be critical for host defense as well as the pathogenesis of autoimmune and autoinflammatory disorders, and serves to link adaptive and innate responses. Recent studies have identified a new subset of T cells that selectively produce IL-17 (Th17 cells; Bettelli, E., T. Korn, and V.K. Kuchroo. 2007. Curr. Opin. Immunol. 19:652–657; Kolls, J.K., and A. Linden. 2004. Immunity. 21:467–476), but the regulation of IL-17 production by innate immune cells is less well understood. We report that in vitro stimulation with IL-23 induced IL-17 production by recombination activating gene (Rag) 2−/− splenocytes but not Rag2−/− common γ chain−/− splenocytes. We found that a major source of IL-17 was CD4+CD3−NK1.1−CD11b−Gr1−CD11c−B220− cells, a phenotype that corresponds to lymphoid tissue inducer–like cells (LTi-like cells), which constitutively expressed the IL-23 receptor, aryl hydrocarbon receptor, and CCR6. In vivo challenge with the yeast cell wall product zymosan rapidly induced IL-17 production in these cells. Genetic deletion of signal transducer and activator of transcription 3 reduced but did not abrogate IL-17 production in LTi-like cells. Thus, it appears that splenic LTi-like cells are a rapid source of IL-17 and IL-22, which might contribute to dynamic organization of secondary lymphoid organ structure or host defense.
Sensing Cardiac Electrical Activity With a Cardiac Myocyte–Targeted Optogenetic Voltage Indicator
Authors: Mei-Ling Chang Liao, Teun P. de Boer, Hiroki Mutoh, Nour Raad, Claudia Richter, Eva Wagner, Bryan R. Downie, Bernhard Unsöld, Iqra Arooj, Katrin Streckfuss-Bömeke, Stephan Döker, Stefan Luther, Kaomei Guan, Stefan Wagner, Stephan E. Lehnart, Lars S. Maier, Walter Stühmer, Erich Wettwer, Toon van Veen, Michael M. Morlock, Thomas Knöpfel, Wolfram-Hubertus Zimmermann
Journal: Circulation Research (2015)

Rationale: Monitoring and controlling cardiac myocyte activity with optogenetic tools offer exciting possibilities for fundamental and translational cardiovascular research. Genetically encoded voltage indicators may be particularly attractive for minimal invasive and repeated assessments of cardiac excitation from the cellular to the whole heart level. Objective: To test the hypothesis that cardiac myocyte–targeted voltage-sensitive fluorescence protein 2.3 (VSFP2.3) can be exploited as optogenetic tool for the monitoring of electric activity in isolated cardiac myocytes and the whole heart as well as function and maturity in induced pluripotent stem cell–derived cardiac myocytes. Methods and Results: We first generated mice with cardiac myocyte–restricted expression of VSFP2.3 and demonstrated distinct localization of VSFP2.3 at the t-tubulus/junctional sarcoplasmic reticulum microdomain without any signs for associated pathologies (assessed by echocardiography, RNA-sequencing, and patch clamping). Optically recorded VSFP2.3 signals correlated well with membrane voltage measured simultaneously by patch clamping. The use of VSFP2.3 for human action potential recordings was confirmed by simulation of immature and mature action potentials in murine VSFP2.3 cardiac myocytes. Optical cardiograms could be monitored in whole hearts ex vivo and minimally invasively in vivo via fiber optics at physiological heart rate (10 Hz) and under pacing-induced arrhythmia. Finally, we reprogrammed tail-tip fibroblasts from transgenic mice and used the VSFP2.3 sensor for benchmarking functional and structural maturation in induced pluripotent stem cell–derived cardiac myocytes. Conclusions: We introduce a novel transgenic voltage-sensor model as a new method in cardiovascular research and provide proof of concept for its use in optogenetic sensing of physiological and pathological excitation in mature and immature cardiac myocytes in vitro and in vivo.
Recovering evolutionary trees under a more realistic model of sequence evolution.
Authors: P J Lockhart, M A Steel, M D Hendy, D Penny
Journal: Molecular Biology and Evolution (1994)

We report a new transformation, the LogDet, that is consistent for sequences with differing nucleotide composition and that have arisen under simple but asymmetric stochastic models of evolution. This transformation is required because existing methods tend to group sequences on the basis of their nucleotide composition, irrespective of their evolutionary history. This effect of differing nucleotide frequencies is illustrated by using a tree-selection criterion on a simple distance measure defined solely on the basis of base composition, independent of the actual sequences. The new LogDet transformation uses determinants of the observed divergence matrices and works because multiplication of determinants (real numbers) is commutative, whereas multiplication of matrices is not,except in special symmetric cases. The use of determinants thus allows more general models of evolution with a symmetric rates of nucleotide change. The transformation is illustrated on a theoretical data set (where existing methods select the wrong tree) and with three biological data sets: chloroplasts, birds/mammals (nuclear), and honeybees ( mitochondrial ) . The LogDet transformation reinforces the logical distinction between transformations on the data and tree-selection criteria. The overall conclusions from this study are that irregular A,C,G,T compositions are an important and possible general cause of patterns that can mislead tree-reconstruction methods, even when high bootstrap values are obtained. Consequently, many published studies may need to be reexamined.
A novel COL1A1 mutation in infantile cortical hyperostosis (Caffey disease) expands the spectrum of collagen-related disorders
Authors: Robert C. Gensure, Outi Mäkitie, Catherine Barclay, Catherine Chan, Steven R. DePalma, Murat Bastepe, Hilal Abuzahra, Richard Couper, Stefan Mundlos, David Sillence, Leena Ala Kokko, Jonathan G. Seidman, William G. Cole, Harald Jüppner
Journal: Journal of Clinical Investigation (2005)

Infantile cortical hyperostosis (Caffey disease) is characterized by spontaneous episodes of subperiosteal new bone formation along 1 or more bones commencing within the first 5 months of life. A genome-wide screen for genetic linkage in a large family with an autosomal dominant form of Caffey disease (ADC) revealed a locus on chromosome 17q21 (LOD score, 6.78). Affected individuals and obligate carriers were heterozygous for a missense mutation (3040C↠T) in exon 41 of the gene encoding the α1(I) chain of type I collagen (COL1A1), altering residue 836 (R836C) in the triple-helical domain of this chain. The same mutation was identified in affected members of 2 unrelated, smaller families with ADC, but not in 2 prenatal cases and not in more than 300 chromosomes from healthy individuals. Fibroblast cultures from an affected individual produced abnormal disulfide-bonded dimeric α1(I) chains. Dermal collagen fibrils of the same individual were larger, more variable in shape and size, and less densely packed than those in control samples. Individuals bearing the mutation, whether they had experienced an episode of cortical hyperostosis or not, had joint hyperlaxity, hyperextensible skin, and inguinal hernias resembling symptoms of a mild form of Ehlers-Danlos syndrome type III. These findings extend the spectrum of COL1A1-related diseases to include a hyperostotic disorder.
Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: a phase II study of the Belgian Group of Digestive Oncology
Authors: I. Borbath, A. Ceratti, C. Verslype, A. Demols, T. Delaunoit, S. Laurent, A. Deleporte, P. Vergauwe, A. Van Maanen, C. Sempoux, E. Van Cutsem, J.L. Van Laethem
Journal: Annals of Oncology (2013)
Concordance for Type 1 Diabetes in Identical Twins Is Affected by Insulin Genotype
Authors: Karl A. Metcalfe, Graham A. Hitman, Rachel E. Rowe, Mohammed Hawa, Xiaojian Huang, Timothy Stewart, R. David G. Leslie
Journal: Diabetes Care (2001)

OBJECTIVE—Monozygotic twins are usually discordant (only one twin affected) for type 1 diabetes. Discordance for disease between such twins implies a role for nongenetically determined factors but could also be influenced by a decreased load of diabetes susceptibility genes. The aim of this study was to determine whether two susceptibility genes were less prevalent in discordant twins compared with concordant twins. RESEARCH DESIGN AND METHODS—We studied 77 monozygotic twin pairs (INS), 40 concordant and 37 discordant, for type 1 diabetes at polymorphism of the insulin gene region on chromosome 11p and HLA-DQBI. RESULTS—The disease-associated INS genotype (Hph I) was identified in 87.5% of the concordant twins but only in 59.5% (P = 0.005) of the discordant twins. Neither DQB1*0201 nor DQB1*0302 was seen in 2 of 40 (5%) concordant twins compared with 8 of 37 (22%) discordant twins (P = 0.04). No statistical differences were seen between concordant and discordant twins at individual alleles of DQB1. Combining insulin and DQ data, 5% of concordant twins compared with 32.4% of discordant twins had neither DQB1*0201/DQB1*0302 nor the high-risk Hph I INS “++” genotype (P = 0.002). CONCLUSIONS—We conclude that the possession of the high-risk Hph I insulin genotype increases the likelihood of identical twins being concordant for type 1 diabetes and that the “load” of both major histocompatibility complex (MHC) and non-MHC susceptibility genes has an impact on the disease penetrance of type 1 diabetes.
Parturition with Fractured Femur
Authors: G. B. Jones
Journal: BMJ (1942)

<h3>Abstract</h3> <h3>Objective</h3> To determine whether restrictiveness-permissiveness of state gun laws or gun ownership are associated with mass shootings in the US. <h3>Design</h3> Cross sectional time series. <h3>Setting and population</h3> US gun owners from 1998-2015. <h3>Exposure</h3> An annual rating between 0 (completely restrictive) and 100 (completely permissive) for the gun laws of all 50 states taken from a reference guide for gun owners traveling between states from 1998 to 2015. Gun ownership was estimated annually as the percentage of suicides committed with firearms in each state. <h3>Main outcome measure</h3> Mass shootings were defined as independent events in which four or more people were killed by a firearm. Data from the Federal Bureau of Investigation’s Uniform Crime Reporting System from 1998-2015 were used to calculate annual rates of mass shootings in each state. Mass shooting events and rates were further separated into those where the victims were immediate family members or partners (domestic) and those where the victims had other relationships with the perpetrator (non-domestic). <h3>Results</h3> Fully adjusted regression analyses showed that a 10 unit increase in state gun law permissiveness was associated with a significant 11.5% (95% confidence interval 4.2% to 19.3%, P=0.002) higher rate of mass shootings. A 10% increase in state gun ownership was associated with a significant 35.1% (12.7% to 62.7%, P=0.001) higher rate of mass shootings. Partially adjusted regression analyses produced similar results, as did analyses restricted to domestic and non-domestic mass shootings. <h3>Conclusions</h3> States with more permissive gun laws and greater gun ownership had higher rates of mass shootings, and a growing divide appears to be emerging between restrictive and permissive states.
Dexamethasone enhances insulin-like growth factor-I effects on skeletal muscle cell proliferation. Role of specific intracellular signaling pathways.
Authors: F Giorgino, R J Smith
Journal: Journal of Clinical Investigation (1995)

IGF-I stimulation of cell proliferation and c-Fos expression in skeletal muscle cells is markedly enhanced by dexamethasone. The effect of dexamethasone is not mediated by changes in IGF-binding proteins, as evidenced by similar effects of dexamethasone on the actions of insulin, PDGF-BB, and the IGF-I analogue long R3IGF-I. Dexamethasone also does not alter autocrine IGF-II secretion by muscle cells. To investigate the mechanism of the augmentation of IGF-I action, the effects of dexamethasone on intracellular IGF-I signaling pathways were determined. In dexamethasone-treated cells, the levels of IGF-I receptor tyrosine phosphorylation and receptor-associated phosphatidylinositol 3-kinase activity were increased. Dexamethasone-treated cells also showed increased and prolonged tyrosine phosphorylation of the Shc proteins. In contrast, dexamethasone decreased both tyrosine phosphorylation and expression of insulin receptor substrate 1 (IRS-1) and IRS-1-associated phosphatidylinositol 3-kinase activity. Thus, distinct signaling pathways activated by the IGF-I receptor in skeletal muscle cells are differentially regulated by dexamethasone. Potentiation of IGF-I action correlates with increased IGF-I receptor-associated phosphatidylinositol 3-kinase activity and tyrosine phosphorylation of Shc, but appears to be independent of activation of the IRS-1/phosphatidylinositol 3-kinase signaling pathway.
THE DISTRIBUTION OF ANTIGENIC DETERMINANTS IN RAT SKIN COLLAGEN
Authors: Herbert Lindsley, Mart Mannik, Paul Bornstein
Journal: The Journal of Experimental Medicine (1971)

Immunological studies of rat skin collagen were carried out with a sensitive and quantitative radioimmunoassay. Hyperimmune rabbit antisera to rat skin collagen and isolated alpha2 chains were used. Iodine-labeled alpha chains and CNBr-produced peptides served as test antigens, and native collagen, alpha chains, and CNBr peptides were employed as inhibitors in the assay. The alpha1 and alpha2 chains were immunologically distinct. Although the alpha1 chain was not immunogenic, antibodies to alpha1 were detected in antisera to the intact collagen molecule. The major antigenic determinant of the alpha1 chain was located in alpha1-CB6 which constitutes the carboxy-terminal region of the chain. The alpha2 chain contained two non-cross-reacting antigenic determinants, one in the amino-terminal region (alpha2-CB1) and the other in the carboxy-terminal region (alpha2-CB5) of the chain. The native collagen molecule was less effective than isolated alpha chains in inhibiting binding of labeled peptides to antisera, indicating that antigenic determinants were less accessible in the triple helical molecule. These immunologic studies are consistent with preliminary comparative biochemical data which indicate that interspecies structural differences in collagen predominate at both the amino- and carboxy-terminal ends of the chains.
Pulmonary alveolar microlithiasis: lung function in five cases
Authors: F. J. D. Fuleihan, R. T. Abboud, J. P. Balikian, C. K. N. Nucho
Journal: Thorax (1969)

Pulmonary function was investigated in five patients with pulmonary alveolar microlithiasis. Four male cases occurred in two families. This contrasts with previous reports that females predominate in familial cases. Only one patient had respiratory symptoms. Total lung capacity was reduced in all patients and vital capacity was less than normal in four of five patients. The ratio of residual volume to total lung capacity and the one second forced expiratory volume was normal in all patients. Frequency of respiration and ventilatory equivalent were greater than normal and tidal volume was less than normal in the symptomatic patient. Minute volume of ventilation, O<sub>2</sub> consumption, and alveolar O<sub>2</sub> tension were normal in all patients. Arterial O<sub>2</sub> tension was less than normal in one patient and became less than normal during exercise in another patient. Arterial CO<sub>2</sub> was low in one patient and arterial <i>p</i>H was normal in all. The alveolar arterial O<sub>2</sub> gradient was greater than normal in all patients; and the venous admixture-like effect was increased in three patients. The ratio of physiological dead space to tidal volume was greater than normal in two patients and the O<sub>2</sub> diffusing capacity was less than normal in one of three patients. Pulmonary function studies reported previously showed no specific pattern. All patients reported herein revealed a definite restrictive pattern with decreased lung volumes, absent airway obstruction, and uneven distribution of pulmonary capillary blood evidenced by an increased alveolar arterial O<sub>2</sub> tension gradient.
Human fetal lymphoid tissue–inducer cells are interleukin 17–producing precursors to RORC+ CD127+ natural killer–like cells
Authors: Tom Cupedo, Natasha K Crellin, Natalie Papazian, Elwin J Rombouts, Kees Weijer, Jane L Grogan, Willem E Fibbe, Jan J Cornelissen, Hergen Spits
Journal: Nature Immunology (2008)
Danazol therapy for cyclic thrombocytopenia
Authors: Rafael Rocha, Lawrence Horstman, Yeon S. Ahn, Ravindra Mylvaganam, William J. Harrington
Journal: American Journal of Hematology (1991)

Abstract Cyclic thrombocytopenia is a rare disease characterized by cyclic oscillations of platelet counts from very low to normal or higher. Severe hemorrhage may occur during the thrombocytopenic phase. To date, treatments for this disorder have been disappointing. Its pathophysiology is unknown. We report a successful outcome using danazol therapy. It can be argued that the long‐term outcome was due to spontaneous remission. However, significant improvement was noted from the outset of danazol therapy, and further improvement with long‐term therapy, as seen in the response of chronic ITP to danazol therapy. Danazol may offer lasting benefit in cyclic thrombocytopenia.
The discovery of endothelins
Authors: T Masaki
Journal: Cardiovascular Research (1998)

Time for primary review 30 days

It is generally accepted that the vascular endothelium is not a simple barrier between the blood stream and vascular bed. It has many functions in the regulation of vascular function that are mediated by various factors released from the endothelium which act on itself or other vascular cells in autocrine and paracrine manners. This concept emerged after the discovery of the endothelium-derived relaxing factor (EDRF) in 1980. The EDRF was later characterized as nitric oxide in 1987. Before the discovery of the EDRF, prostacycline was discovered, which is also a relaxing factor produced by the endothelium. These two relaxing factors are released from endothelial cells in response to a variety of vasoactive substances, and are thought to regulate vascular tone.

In contrast to endothelium-derived relaxing factors, less progress had been made in the field of endothelium-derived constricting factors such as thromboxane, a strong vasoconstrictor which is produced in the endothelium.

In 1985, Hickey et al. reported the existence of a vasoconstricting factor in a conditioned medium of cultured bovine endothelial cells [1]. They suggested that the factor was a peptide. In May 1987, we started purification and identification of this factor. We collected a large amount of conditioned medium of cultured bovine endothelial cells which contained the factor, and were able to quickly isolate the factor and determine the whole sequence of the peptide. We organized an excellent group to promote this project, and Yanagisawa, Kuribara, Goto and Kimura were involved. Kimura is an expert of peptide chemistry, Goto is a pharmacologist, and both Yanagisawa and Kurihara are excellent active investigators. They finished the purification of the factor by the end of July, which was followed by amino acid sequence analysis and cDNA cloning of the peptide. Both experiments were quickly finished, and …
Mouse lung regeneration after H1N1
Authors: Imran Mahmud
Journal: Thorax (2011)

This study demonstrates that following an ARDS-like syndrome in mice secondary to infection with a murine-adapted H1N1 virus, complete recovery follows the emergence of a population of stem cells bearing the differentiation markers of alveoli.

Contrary to the existing bleomycin-based models of pulmonary injury causing fibrosis, this murine H1N1 model sustains substantial airway damage and epithelial destruction, followed by …