tbuckley/cabot-search huggingface dataset:
Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice.
Authors: L Boring, J Gosling, S W Chensue, S L Kunkel, R V Farese, H E Broxmeyer, I F Charo
Journal: Journal of Clinical Investigation (1997)

Monocyte chemoattractant protein-1 (MCP-1) is a potent agonist for mononuclear leukocytes and has been implicated in the pathogenesis of atherosclerosis and granulomatous lung disease. To determine the role of MCP-1 and related family members in vivo, we used homologous recombination in embryonic stem cells to generate mice with a targeted disruption of C-C chemokine receptor 2 (CCR2), the receptor for MCP-1. CCR2-/- mice were born at the expected Mendelian ratios and developed normally. In response to thioglycollate, the recruitment of peritoneal macrophages decreased selectively. In in vitro chemotaxis assays, CCR2-/- leukocytes failed to migrate in response to MCP-1. Granulomatous lung disease was induced in presensitized mice by embolization with beads coupled to purified protein derivative (PPD) of Mycobacterium bovis. As compared with wild-type littermates, CCR2-/- mice had a decrease in granuloma size accompanied by a dramatic decrease in the level of interferon gamma in the draining lymph nodes. Production of interferon gamma was also decreased in PPD-sensitized splenocytes from CCR2-/- mice and in naive splenocytes activated by concanavalin A. We conclude that CCR2-/- mice have significant defects in both delayed-type hypersensitivity responses and production of Th1-type cytokines. These data suggest an important and unexpected role for CCR2 activation in modulating the immune response, as well as in recruiting monocytes/macrophages to sites of inflammation.
The novel<i>SLCO2A1</i>heterozygous missense mutation p.E427K and nonsense mutation p.R603* in a female patient with pachydermoperiostosis with an atypical phenotype
Authors: H. Niizeki, A. Shiohama, T. Sasaki, A. Seki, K. Kabashima, A. Otsuka, M. Takeshita, A. Hirakiyama, T. Okuyama, K. Tanese, A. Ishiko, M. Amagai, J. Kudoh
Journal: British Journal of Dermatology (2013)
The effects of lidocaine and quinidine on impulse propagation across the canine Purkinje-muscle junction during combined hyperkalemia, hypoxia, and acidosis.
Authors: J J Evans, R F Gilmour, D P Zipes
Journal: Circulation Research (1984)

During ischemia, lidocaine or quinidine may prevent arrhythmias by blocking conduction without suppressing abnormal automaticity. The purpose of this study was to determine whether lidocaine or quinidine (5 micrograms/ml) produced Purkinje fiber-papillary muscle block during superfusion in vitro with an altered Tyrode's solution containing some components of ischemia: 6 mM potassium, PO2 less than 40, pH = 6.8. Unbranched canine Purkinje fibers connected to papillary muscle at one end were threaded through a three-chamber bath with Purkinje fiber-papillary muscle in the left chamber and Purkinje fiber alone in the middle and right chambers. Action potentials were recorded using microelectrodes from Purkinje fiber, papillary muscle, and cells at the Purkinje fiber-papillary muscle junction. Purkinje fiber or papillary muscle was stimulated at 1.5-4 Hz. Perfusion of the left chamber with altered Tyrode's solution decreased resting membrane potential, action potential amplitude, and the maximum rate of rise of phase 0 of the action potential of Purkinje fiber, papillary muscle, and junctional cells, and prolonged activation times of junctional cells and papillary muscle; but action potentials propagated from Purkinje fiber to papillary muscle, and from papillary muscle to Purkinje fiber. Lidocaine or quinidine plus altered Tyrode's solution further decreased action potential amplitude and the maximum rate of rise of phase 0 of the action potential of Purkinje fiber, papillary muscle, and junctional cells, and prolonged activation of junctional cells and papillary muscle, inducing bidirectional block only at the Purkinje fiber-papillary muscle junction. Lidocaine or quinidine plus normal Tyrode's solution and each component of altered Tyrode's solution alone did not produce block. Perfusion of the right chamber with 0.25 mM barium induced Purkinje fiber automaticity that: propagated to papillary muscle during perfusion of the left chamber with normal Tyrode's or altered Tyrode's solution; blocked at the Purkinje fiber-papillary muscle junction during perfusion of the left chamber with altered Tyrode's solution plus lidocaine; and was not suppressed during perfusion of the right chamber with lidocaine. Thus, lidocaine or quinidine may produce bidirectional block at Purkinje fiber-papillary muscle junction and interrupt a potential limb of a reentrant circuit without suppressing automatic arrhythmogenic foci.
Phenobarbital Influences the Development of Sodium Retention in Liver Disease Induced by Bile Duct Ligation in the Rat
Authors: Georg Wensing, Robert A. Branch
Journal: Hepatology (1990)

The onset of sodium retention in phenobarbital/carbon tetrachloride-induced cirrhosis in rats is preceded by a linear decrease in hepatic function as assessed by the aminopyrine rate constant of elimination. Sodium retention occurs when liver function decreases below a critical aminopyrine rate constant of elimination threshold of 1 min-1 x 10(-3). The objective of this study was to investigate this relationship in a different experimental model of cirrhosis in rats and to learn whether alteration of drug-metabolizing activity by hepatic enzyme induction changes the threshold for urinary sodium retention. Cirrhosis was induced in untreated and phenobarbital-treated rats by bile duct excision. Liver function, assessed by the aminopyrine breath test, and urinary sodium excretion on a constant salt diet were measured weekly for up to 4 wk. In untreated rats, the aminopyrine breath test rate constant of elimination was reduced by about 40% within 1 wk of surgery. Aminopyrine rate constant of elimination then decreased more slowly, but linearly. Urinary sodium excretion was initially unchanged, but sodium retention occurred after 2.5 wk and was maintained until the end of the experiment. Phenobarbital-treated rats had greater initial aminopyrine rate constant of elimination, but we saw a similar fall in aminopyrine rate constant of elimination of about 40% within 1 wk of bile duct excision to a value still above baseline aminopyrine rate constant of elimination of untreated controls. Aminopyrine rate constant of elimination remained at a plateau for 3.5 wk without changes in urinary sodium excretion. After 3.5 wk, a sudden decrease in aminopyrine rate constant of elimination was associated with the sudden onset of sodium retention.(ABSTRACT TRUNCATED AT 250 WORDS)
Contemporary murine models in preclinical astrocytoma drug development
Authors: Robert S. McNeill, Mark Vitucci, Jing Wu, C. Ryan Miller
Journal: Neuro-Oncology (2014)

Despite 6 decades of research, only 3 drugs have been approved for astrocytomas, the most common malignant primary brain tumors. However, clinical drug development is accelerating with the transition from empirical, cytotoxic therapy to precision, targeted medicine. Preclinical animal model studies are critical for prioritizing drug candidates for clinical development and, ultimately, for their regulatory approval. For decades, only murine models with established tumor cell lines were available for such studies. However, these poorly represent the genomic and biological properties of human astrocytomas, and their preclinical use fails to accurately predict efficacy in clinical trials. Newer models developed over the last 2 decades, including patient-derived xenografts, genetically engineered mice, and genetically engineered cells purified from human brains, more faithfully phenocopy the genomics and biology of human astrocytomas. Harnessing the unique benefits of these models will be required to identify drug targets, define combination therapies that circumvent inherent and acquired resistance mechanisms, and develop molecular biomarkers predictive of drug response and resistance. With increasing recognition of the molecular heterogeneity of astrocytomas, employing multiple, contemporary models in preclinical drug studies promises to increase the efficiency of drug development for specific, molecularly defined subsets of tumors.
Tissue Discontinuities Affect Conduction Velocity Restitution
Authors: Richard Derksen, Harold V.M. van Rijen, Ronald Wilders, Sara Tasseron, Richard N.W. Hauer, Willem L.C. Rutten, Jacques M.T. de Bakker
Journal: Circulation (2003)

The mechanism by which structural barriers promote wave break and fibrillation is unclear. Conduction velocity (CV) restitution is an important determinant of wave break. Abnormal CV restitution is associated with ventricular fibrillation in patients with heart disease and arises preferentially in fibrotic myocardium. We hypothesize that tissue discontinuities imposed by structural barriers cause abnormal CV restitution.Tissue discontinuities were simulated in cultures of neonatal rat heart cells grown in 8-armed star patterns. Premature stimulation was applied at the extremity of 1 arm (n=12) while extracellular electrograms were recorded at 24 sites throughout the star. Action potentials were recorded at the following 3 sites: in the stimulated arm and at the discontinuity both proximal to and distal from the star center. Extracellular recordings revealed progressive increases in activation delay (indicative for abnormal CV restitution) only at the discontinuity from arms proximal to the star center. The mean increase in delay was 0.81+/-0.41 ms/10 ms for recording sites proximal to and 3.13+/-0.58 ms/10 ms for sites distal from this discontinuity. Depolarizing currents were determined in single cells during premature stimulation and for voltage configurations similar to those arising at the discontinuity. Both voltage-clamp measurements and computer simulations showed that delay at the discontinuity was associated with biphasic, prolonged activation and delayed inactivation of depolarizing current.Tissue discontinuities cause abnormal CV restitution. Rapid increase in activation after an initial slow activation and delayed inactivation at the discontinuity lengthen the duration of depolarizing current and cause the abnormal restitution.
The Epidemiologic Basis for the Prevention of Firearm Injuries
Authors: Arthur L. Kellermann, Roberta K. Lee, James A. Mercy, Joyce Banton
Journal: Annual Review of Public Health (1991)

In recent decades, there has been remarkable growth in scientific research examining the multiple ways in which racism can adversely affect health. This interest has been driven in part by the striking persistence of racial/ethnic inequities in health and ...Read More
Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp.
Authors: M Matsuda, R A DeFronzo
Journal: Diabetes Care (1999)

Several methods have been proposed to evaluate insulin sensitivity from the data obtained from the oral glucose tolerance test (OGTT). However, the validity of these indices has not been rigorously evaluated by comparing them with the direct measurement of insulin sensitivity obtained with the euglycemic insulin clamp technique. In this study, we compare various insulin sensitivity indices derived from the OGTT with whole-body insulin sensitivity measured by the euglycemic insulin clamp technique.In this study, 153 subjects (66 men and 87 women, aged 18-71 years, BMI 20-65 kg/m2) with varying degrees of glucose tolerance (62 subjects with normal glucose tolerance, 31 subjects with impaired glucose tolerance, and 60 subjects with type 2 diabetes) were studied. After a 10-h overnight fast, all subjects underwent, in random order, a 75-g OGTT and a euglycemic insulin clamp, which was performed with the infusion of [3-3H]glucose. The indices of insulin sensitivity derived from OGTT data and the euglycemic insulin clamp were compared by correlation analysis.The mean plasma glucose concentration divided by the mean plasma insulin concentration during the OGTT displayed no correlation with the rate of whole-body glucose disposal during the euglycemic insulin clamp (r = -0.02, NS). From the OGTT, we developed an index of whole-body insulin sensitivity (10,000/square root of [fasting glucose x fasting insulin] x [mean glucose x mean insulin during OGTT]), which is highly correlated (r = 0.73, P < 0.0001) with the rate of whole-body glucose disposal during the euglycemic insulin clamp.Previous methods used to derive an index of insulin sensitivity from the OGTT have relied on the ratio of plasma glucose to insulin concentration during the OGTT. Our results demonstrate the limitations of such an approach. We have derived a novel estimate of insulin sensitivity that is simple to calculate and provides a reasonable approximation of whole-body insulin sensitivity from the OGTT.
Potentiation by Carbon Tetrachloride of the Immunosuppressive Effects of Fibrosarcoma and Toxic Material Produced by Fibrosarcoma Cells2
Authors: A. O. B. Wong, R. Mankovitz, J. C. Kennedy
Journal: JNCI Journal of the National Cancer Institute (1975)

SaD2-AG fibrosarcomas growing in DBA/2 mice caused nonspecific immunodepression. Injection of soluble material produced by cultured SaD2-AG cells into normal DBA/2 recipients caused nonspecific immunodepression and signs of systemic toxicity. These in vivo effects were enhanced by prior treatment of the recipients with carbon tetrachloride (CCl4). In contrast, material released by syngeneic fibroblasts was neither immunosuppressive nor toxic to normal mice or mice previously treated with CCl4. A soluble toxic material released by the fibrosarcoma cells may be responsible for at least some of the systemic effects of localized SaD2-AG tumors growing at a site not involving vital structures, and a protective host mechanism whose maximum capacity can be decreased by the administration of CCl4 may minimize the toxic effects of the cancer-derived material.
A genome-wide association study in Chinese men identifies three risk loci for non-obstructive azoospermia
Authors: Zhibin Hu, Yankai Xia, Xuejiang Guo, Juncheng Dai, HongGang Li, Hongliang Hu, Yue Jiang, Feng Lu, Yibo Wu, Xiaoyu Yang, Huizhang Li, Bing Yao, Chuncheng Lu, Chenliang Xiong, Zheng Li, Yaoting Gui, Jiayin Liu, Zuomin Zhou, Hongbing Shen, Xinru Wang, Jiahao Sha
Journal: Nature Genetics (2011)
Proteomic screening identifies a YAP-driven signaling network linked to tumor cell proliferation in human schwannomas
Authors: Alizée Boin, Anne Couvelard, Christophe Couderc, Isabel Brito, Dan Filipescu, Michel Kalamarides, Pierre Bedossa, Leanne De Koning, Carine Danelsky, Thierry Dubois, Philippe Hupé, Daniel Louvard,, Dominique Lallemand
Journal: Neuro-Oncology (2014)

Inactivation of the NF2 gene predisposes to neurofibromatosis type II and the development of schwannomas. In vitro studies have shown that loss of NF2 leads to the induction of mitogenic signaling mediated by receptor tyrosine kinases (RTKs), MAP kinase, AKT, or Hippo pathways. The goal of our study was to evaluate the expression and activity of these signaling pathways in human schwannomas in order to identify new potential therapeutic targets.Large sets of human schwannomas, totaling 68 tumors, were analyzed using complementary proteomic approaches. RTK arrays identified the most frequently activated RTKs. The correlation between the expression and activity of signaling pathways and proliferation of tumor cells using Ki67 marker was investigated by reverse-phase protein array (RRPA). Finally, immunohistochemistry was used to evaluate the expression pattern of signaling effectors in the tumors.We showed that Her2, Her3, PDGFRß, Axl, and Tie2 are frequently activated in the tumors. Furthermore, RRPA demonstrated that Ki67 levels are linked to YAP, p-Her3, and PDGFRß expression levels. In addition, Her2, Her3, and PDGFRß are transcriptional targets of Yes-associated protein (YAP) in schwannoma cells in culture. Finally, we observed that the expression of these signaling effectors is very variable between tumors.Tumor cell proliferation in human schwannomas is linked to a signaling network controlled by the Hippo effector YAP. Her2, Her3, PDGFRß, Axl, and Tie2, as well as YAP, represent potentially valuable therapeutic targets. However, the variability of their expression between tumors may result in strong differences in the response to targeted therapy.
THRESHOLD OF RESPONSE OF THE CEREBRAL VESSELS OF MAN TO INCREASE IN BLOOD CARBON DIOXIDE 1
Authors: John L. Patterson, Albert Heyman, Louis L. Battey, Robert W. Ferguson
Journal: Journal of Clinical Investigation (1955)

The level of carbon dioxide in the blood is now generally accepted as one of the major factors in the regulation of the cerebral circulation.It was first shown in experimental animals that increase in blood carbon dioxide exerts a vasodilator effect on cerebral blood vessels (1, 2).Similar effects were postulated in man by Lennox and Gibbs (3) on the basis of decrease in the cerebral arteriovenous oxygen difference.Conclusive evidence of the effects of carbon dioxide on cerebral blood flow in man was provided by the experiments of Kety and Schmidt with the nitrous oxide method.Reduction in arterial CO2 through hyperventilation was shown to produce a decrease in blood flow, (4) whereas increase in arterial CO2 through inhalation of 5 per cent and 7 per cent carbon diox- ide was found to cause a striking increase in blood flow (5).The above observations on man, which were concerned with large-scale effects, do not in them- selves permit a precise formulation of the role of carbon dioxide in the control of the cerebral cir- culation.The minimal changes in blood CO2 which will evoke vascular responses must be known, together with the degrees of response which are produced by given increments of change in CO2 beyond these threshold values.Knowledge of the minimal increase in arterial CO2 required to dilate cerebral vessels has potential therapeutic application in the treatment of certain states of severe impairment of blood flow to the brain.Carbon dioxide in 5 per cent or greater concentra-
Two-Year Outcomes after Conventional or Endovascular Repair of Abdominal Aortic Aneurysms
Authors: Jan D. Blankensteijn, Sjors E.C.A. de Jong, Monique Prinssen, Arie C. van der Ham, Jaap Buth, Steven M.M. van Sterkenburg, Hence J.M. Verhagen, Erik Buskens, Diederick E. Grobbee
Journal: New England Journal of Medicine (2005)

Two randomized trials have shown better outcomes with elective endovascular repair of abdominal aortic aneurysms than with conventional open repair in the first month after the procedure. We investigated whether this advantage is sustained beyond the perioperative period.We conducted a multicenter, randomized trial comparing open repair with endovascular repair in 351 patients who had received a diagnosis of abdominal aortic aneurysm of at least 5 cm in diameter and who were considered suitable candidates for both techniques. Survival after randomization was calculated with the use of Kaplan-Meier analysis and compared with the use of the log-rank test on an intention-to-treat-basis.Two years after randomization, the cumulative survival rates were 89.6 percent for open repair and 89.7 percent for endovascular repair (difference, -0.1 percentage point; 95 percent confidence interval, -6.8 to 6.7 percentage points). The cumulative rates of aneurysm-related death were 5.7 percent for open repair and 2.1 percent for endovascular repair (difference, 3.7 percentage points; 95 percent confidence interval, -0.5 to 7.9 percentage points). This advantage of endovascular repair over open repair was entirely accounted for by events occurring in the perioperative period, with no significant difference in subsequent aneurysm-related mortality. The rate of survival free of moderate or severe complications was also similar in the two groups at two years (at 65.9 percent for open repair and 65.6 percent for endovascular repair; difference, 0.3 percentage point; 95 percent confidence interval, -10.0 to 10.6 percentage points).The perioperative survival advantage with endovascular repair as compared with open repair is not sustained after the first postoperative year.
Epithelial to Mesenchymal Transition in Human Breast Epithelial Cells Transformed by 17β-Estradiol
Authors: Yong Huang, Sandra V. Fernandez, Shirlean Goodwin, Patricia A. Russo, Irma H. Russo, Thomas R. Sutter, Jose Russo
Journal: Cancer Research (2007)

Abstract The estrogen dependence of breast cancer has long been recognized; however, the role of 17β-estradiol (E2) in cancer initiation was not known until we showed that it induces complete neoplastic transformation of the human breast epithelial cells MCF-10F. E2 treatment of MCF-10F cells progressively induced high colony efficiency and loss of ductulogenesis in early transformed (trMCF) cells and invasiveness in Matrigel invasion chambers. The cells that crossed the chamber membrane were collected and identified as bsMCF; their subclones were designated bcMCF; and the cells harvested from carcinoma formation in severe combined immunodeficient mice were designated caMCF. These phenotypes correlated with gene dysregulation during the progression of the transformation. The highest number of dysregulated genes was observed in caMCF, being slightly lower in bcMCF, and lowest in trMCF. This order was consistent with the extent of chromosome aberrations (caMCF &amp;gt; bcMCF &amp;gt;&amp;gt;&amp;gt; trMCF). Chromosomal amplifications were found in 1p36.12-pter, 5q21.1-qter, and 13q21.31-qter. Losses of the complete chromosome 4 and 8p11.21-23.1 were found only in tumorigenic cells. In tumor-derived cell lines, additional losses were found in 3p12.1-14.1, 9p22.1-pter, and 18q11.21-qter. Functional profiling of dysregulated genes revealed progressive changes in the integrin signaling pathway, inhibition of apoptosis, acquisition of tumorigenic cell surface markers, and epithelial-mesenchymal transition. In tumorigenic cells, the levels of E-cadherin, epithelial membrane antigen, and various keratins were low and CD44E/CD24 were negative, whereas SNAI2, vimentin, S100A4, FN1, HRAS, transforming growth factor β1, and CD44H were high. The phenotypic and genomic changes triggered by estrogen exposure that lead normal cells to tumorigenesis confirm the role of this steroid hormone in cancer initiation. [Cancer Res 2007;67(23):11147–57]