tbuckley/cabot-search huggingface dataset:
An Epithelial–Mesenchymal Transition Gene Signature Predicts Resistance to EGFR and PI3K Inhibitors and Identifies Axl as a Therapeutic Target for Overcoming EGFR Inhibitor Resistance
Authors: Lauren Averett Byers, Lixia Diao, Jing Wang, Pierre Saintigny, Luc Girard, Michael Peyton, Li Shen, Youhong Fan, Uma Giri, Praveen K. Tumula, Monique B. Nilsson, Jayanthi Gudikote, Hai Tran, Robert J.G. Cardnell, David J. Bearss, Steven L. Warner, Jason M. Foulks, Steven B. Kanner, Varsha Gandhi, Nancy Krett, Steven T. Rosen, Edward S. Kim, Roy S. Herbst, George R. Blumenschein, J. Jack Lee, Scott M. Lippman, K. Kian Ang, Gordon B. Mills, Waun K. Hong, John N. Weinstein, Ignacio I. Wistuba, Kevin R. Coombes, John D. Minna, John V. Heymach
Journal: Clinical Cancer Research (2012)

Epithelial-mesenchymal transition (EMT) has been associated with metastatic spread and EGF receptor (EGFR) inhibitor resistance. We developed and validated a robust 76-gene EMT signature using gene expression profiles from four platforms using non-small cell lung carcinoma (NSCLC) cell lines and patients treated in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) study.We conducted an integrated gene expression, proteomic, and drug response analysis using cell lines and tumors from patients with NSCLC. A 76-gene EMT signature was developed and validated using gene expression profiles from four microarray platforms of NSCLC cell lines and patients treated in the BATTLE study, and potential therapeutic targets associated with EMT were identified.Compared with epithelial cells, mesenchymal cells showed significantly greater resistance to EGFR and PI3K/Akt pathway inhibitors, independent of EGFR mutation status, but more sensitivity to certain chemotherapies. Mesenchymal cells also expressed increased levels of the receptor tyrosine kinase Axl and showed a trend toward greater sensitivity to the Axl inhibitor SGI-7079, whereas the combination of SGI-7079 with erlotinib reversed erlotinib resistance in mesenchymal lines expressing Axl and in a xenograft model of mesenchymal NSCLC. In patients with NSCLC, the EMT signature predicted 8-week disease control in patients receiving erlotinib but not other therapies.We have developed a robust EMT signature that predicts resistance to EGFR and PI3K/Akt inhibitors, highlights different patterns of drug responsiveness for epithelial and mesenchymal cells, and identifies Axl as a potential therapeutic target for overcoming EGFR inhibitor resistance associated with the mesenchymal phenotype.
Impairment of Sodium Balance in Mice Deficient in Renal Principal Cell Mineralocorticoid Receptor
Authors: Caroline Ronzaud, Johannes Loffing, Markus Bleich, Norbert Gretz, Hermann-Josef Gröne, Günther Schütz, Stefan Berger
Journal: Journal of the American Society of Nephrology (2007)

Germline inactivation of the mineralocorticoid receptor (MR) gene in mice results in postnatal lethality as a result of massive loss of sodium and water. The knockout mice show impaired epithelial sodium channel (ENaC) activity in kidney and colon. For determination of the role of renal MR in aldosterone-driven ENaC-mediated sodium reabsorption, mice with principal cell MR deficiency were generated using the Cre-loxP system. For driving Cre recombinase expression in principal cells, the regulatory elements of the mouse aquaporin 2 (AQP2) gene were used. Mutant mice (MRAQP2Cre) were obtained by crossing AQP2Cre mice with mice that carried a conditional MR allele. Under standard diet, MRAQP2Cre mice develop normally and exhibit unaltered renal sodium excretion but show strongly elevated aldosterone levels. Increased renal sodium and water excretion, resulting in continuous loss of body weight, occur under low-sodium diet. Immunofluorescence revealed that the loss of MR and apical ENaC staining is restricted to principal cells of the collecting duct (CD) and late connecting tubule (CNT) and that MR is crucial for ENaC trafficking to the apical membrane. These results demonstrate that inactivation of MR in CD and late CNT can be compensated under standard diet but no longer when sodium supply is limited. Because the mutant mice show preserved renal ENaC activity, this study provides evidence that the late distal convoluted tubule and early CNT can compensate to a large extent deficient ENaC-mediated sodium reabsorption in late CNT and CD.
Expression of a new cell surface antigen on activated murine macrophages.
Authors: A M Kaplan, T Mohanakumar
Journal: The Journal of Experimental Medicine (1977)

A macrophage cell-surface antigen associated with pyran and Corynebacterium parvum-activated macrophages and P388D1 cells but not detectable on normal or glycogen and thioglycollate-elicited murine macrophages has been described. The antigen was demonstrated both by complement-mediated cytotoxicity and immunofluorescence, using an appropriately absorbed rabbit antiserum to P388D1. This antiserum should enable the characterization of activated macrophage cell populations on an individual cell basis and should be a useful probe to study the interactions of macrophages with tumor cells and the relationship of activation to cell-surface changes.
Points: Pancreatic endocrine tumours
Authors: A. P Hemingway, D. J Allison
Journal: BMJ (1987)

Professor D C Carter (7 March, p 593) com- ments on the treatment of hepatic metastases by surgical debulking, but the value of hepatic arterial embolisation is not mentioned.'2In our experience, when vascular endocrine metastases are detected in the liver, providing that the intrahepatic portal veins are patent, hepatic arterial embolisation can provide
Detection of chromatin-associated single-stranded DNA in regions targeted for somatic hypermutation
Authors: Diana Ronai, Maria D. Iglesias-Ussel, Manxia Fan, Ziqiang Li, Alberto Martin, Matthew D. Scharff
Journal: The Journal of Experimental Medicine (2007)

After encounter with antigen, the antibody repertoire is shaped by somatic hypermutation (SHM), which leads to an increase in the affinity of antibodies for the antigen, and class-switch recombination (CSR), which results in a change in the effector function of antibodies. Both SHM and CSR are initiated by activation-induced cytidine deaminase (AID), which deaminates deoxycytidine to deoxyuridine in single-stranded DNA (ssDNA). The precise mechanism responsible for the formation of ssDNA in V regions undergoing SHM has yet to be experimentally established. In this study, we searched for ssDNA in mutating V regions in which DNA–protein complexes were preserved in the context of chromatin in human B cell lines and in primary mouse B cells. We found that V regions that undergo SHM were enriched in short patches of ssDNA, rather than R loops, on both the coding and noncoding strands. Detection of these patches depended on the presence of DNA-associated proteins and required active transcription. Consistent with this, we found that both DNA strands in the V region were transcribed. We conclude that regions of DNA that are targets of SHM assemble protein–DNA complexes in which ssDNA is exposed, making it accessible to AID.
A multinational phase II trial of bevacizumab with low-dose interferon-α2a as first-line treatment of metastatic renal cell carcinoma: BEVLiN
Authors: B. Melichar, S. Bracarda, V. Matveev, B. Alekseev, S. Ivanov, A. Zyryanov, R. Janciauskiene, E. Fernebro, P. Mulders, S. Osborne, S. Jethwa, G. Mickisch, M. Gore, R.J.A. van Moorselaar, M. Staehler, N. Magne, J. Bellmunt
Journal: Annals of Oncology (2013)
Long-Term Clinical Course of Patients After Termination of Ventricular Tachyarrhythmia by an Implanted Defibrillator
Authors: Arthur J. Moss, Henry Greenberg, Robert B. Case, Wojciech Zareba, W. Jackson Hall, Mary W. Brown, James P. Daubert, Scott McNitt, Mark L. Andrews, Adam D. Elkin
Journal: Circulation (2004)

The implanted cardioverter defibrillator (ICD) improves survival in high-risk cardiac patients. This analysis from the MADIT-II trial database examines the long-term clinical course and subsequent mortality risk of patients after termination of life-threatening ventricular tachyarrhythmias by an ICD.Life-table survival analysis was performed, and proportional hazards regression analysis was used to evaluate the contribution of baseline clinical factors and time-dependent defibrillator therapy to mortality during long-term follow-up. Of 720 patients with an ICD (average follow-up 21 months), 169 patients received 701 antiarrhythmic device therapies for ventricular tachyarrhythmias. Few baseline characteristics distinguished patients who received appropriate ICD therapy for their first ventricular tachyarrhythmic episode. The probability of survival for at least 1 year after first therapy for ventricular tachycardia (VT) or ventricular fibrillation (VF) was 80%. The hazard ratios for the risk of death due to any cause in those who survived appropriate therapy for termination of VT and VF were 3.4 (P<0.001) and 3.3 (P=0.01), respectively, compared with those who survived without receiving ICD therapy, with a high frequency of heart failure and late nonsudden cardiac death after first successful ICD therapy for VF.Successful appropriate therapy by an ICD for VT or VF is associated with 80% survival at 1 year after arrhythmia termination. These patients are at increased risk for heart failure and nonsudden cardiac death after device termination of VT or VF and should receive special attention for the prevention and management of progressive left ventricular dysfunction during long-term follow-up.
A simple cooling circuit for topical cardiac hypothermia.
Authors: D R Wheeldon, D W Bethune, R D Gill, T A English
Journal: Thorax (1976)

Rapid uniform cooling of the heart is the most important requirement of any method using local hypothermia for protection of the myocardium during open intracardiac surgery. We report the construction and operation of a recirculation cooling circuit comprising a reservoir, pump, and heat-exchanger for this purpose. It is operated by the perfusionist and can deliver up to 1 litre of fluid per minute at 4 degrees C into the pericardium or interior of the heart. Advantages of the system include rapid cooling of the myocardium, simplicity of operation, and applicability to all routine cardiac surgical procedures.
Coordination of Mesangial Cell Contraction by Gap Junction–Mediated Intercellular Ca2+ Wave
Authors: Jian Yao, Tetsuo Morioka, Bing Li, Takashi Oite
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. Gap junction intercellular communication (GJIC) plays a fundamental role in mediating intercellular signals and coordinating multicellular behavior in various tissues and organs. Glomerular mesangial cells (MC) are rich in GJ, but the functional associations of these intercellular channels are still unclear. This study examines the potential role of GJ in the transmission of intercellular Ca2+ signals and in the coordination of MC contraction. First, the presence of GJ protein Cx43 and functional GJIC was confirmed in MC by using immunochemical staining or transfer of Lucifer yellow (LY) after a single cell injection, respectively. Second, mechanical stimulation of a single MC initiated propagation of an intercellular Ca2+ wave, which was preventable by the GJ inhibitor heptanol but was not altered by pretreatment of MC with ATP or addition of apyrase into the assay system. Third, the phospholipase C (PLC) inhibitor U73122 could largely eliminate the mechanically elicited propagation of intercellular Ca2+ waves, suggesting a possibly mediating role of inositol trisphosphate (IP3) in the initiation and transmission of intercellular Ca2+ signaling. Fourth, injection of IP3 into a single cell caused contraction, not only in the targeted cell, but also in the adjacent cells, as indicated by the reduction of cellular planar area. Fifth, addition of two structurally unrelated GJ inhibitors, heptanol and α-glycyrrhetinic acid (GA), into MC embedded in collagen gels significantly attenuated the reduction of gel areas after exposure to serum. This study provides the first functional evidence supporting the critical role of GJIC in the synchronization of MC behaviors.
Sequential development of interleukin 2–dependent effector and regulatory T cells in response to endogenous systemic antigen
Authors: Birgit Knoechel, Jens Lohr, Estelle Kahn, Jeffrey A. Bluestone, Abul K. Abbas
Journal: The Journal of Experimental Medicine (2005)

Transfer of naive antigen-specific CD4+ T cells into lymphopenic mice that express an endogenous antigen as a systemic, secreted protein results in severe autoimmunity resembling graft-versus-host disease. T cells that respond to this endogenous antigen develop into effector cells that cause the disease. Recovery from this disease is associated with the subsequent generation of FoxP3+CD25+ regulatory cells in the periphery. Both pathogenic effector cells and protective regulatory cells develop from the same antigen-specific T cell population after activation, and their generation may occur in parallel or sequentially. Interleukin (IL)-2 plays a dual role in this systemic T cell reaction. In the absence of IL-2, the acute disease is mild because of reduced T cell effector function, but a chronic and progressive disease develops late and is associated with a failure to generate FoxP3+ regulatory T (T reg) cells in the periphery. Thus, a peripheral T cell reaction to a systemic antigen goes through a phase of effector cell–mediated pathology followed by T reg cell–mediated recovery, and both require the growth factor IL-2.
Liquid ventilation in the preterm neonate
Authors: C. W. Yoxall, N. V. Subhedar, N. J. Shaw
Journal: Thorax (1997)

Background.The intratracheal administration of a perfluorocarbon liquid during continuous positivepressure ventilation (partial liquid ventilation) improves lung function in animals with surfactant deficiency.Whether partial liquid ventilation is effective in the treatment of infants with severe respiratory distress syndrome is not known.Methods.We studied the efficacy of partial liquid ventilation with perflubron in 13 premature infants with severe respiratory distress syndrome in whom conventional treatment, including surfactant therapy, had failed.Partial liquid ventilation was initiated by instilling perflubron during conventional mechanical ventilation to a volume approximating the functional residual capacity.Infants were considered to have completed the study if they received partial liquid ventilation for at least 24 hours.Results.Ten infants received partial liquid ventilation for 24 to 76 hours.In the other three infants, partial liquid ventilation was discontinued within four hours in favor of high-frequency ventilation, which was not permitted by the protocol, and the data from these infants were excluded from the analysis.Within one hour after the instillation of perflubron, the arterial oxygen tension increased by 138 percent and the dynamic compliance increased by 61 percent; the mean (±SD) oxygenation index was reduced from 49±60 to 17±16.Chest radiographs showed symmetric filling, with patchy clearing during the return from partial liquid to gas ventilation.There were no adverse events clearly attributable to partial liquid ventilation.Infants were weaned from partial liquid to gas ventilation without complications.Eight infants survived to 36 weeks' corrected gestational age.Conclusions.Partial liquid ventilation leads to clinical improvement and survival in some infants with severe respiratory distress syndrome who are not predicted to survive.
Seasonal variation in community-acquired pneumonia
Authors: D Lieberman, D Lieberman, A Porath
Journal: European Respiratory Journal (1996)

Seasonal variation in the incidence of disease in general, and of infectious diseases in particular, is vitally important information for epidemiologists and for clinicians who deal with these diseases. In relation to community-acquired pneumonia (CAP), the seasonal distribution of the disease and, in particular, of each of the specific aetiological agents is important. All 346 adult patients who were admitted to a regional hospital in southern Israel for CAP over a period of 1 year were included in a prospective study. As part of the study, a comprehensive diagnostic work-up was performed to identify the specific causative agents for CAP. The study findings were analysed and are presented in terms of the seasonal distribution of the disease. Thirty four percent of CAP cases occurred in the spring and only 18% in the autumn (p = 0.036). Respiratory viruses CAP were predominant in the winter and spring (p = 0.009), whilst Mycoplasma pneumoniae CAP reached its peak incidence of 41% in the spring compared with 15% during the winter months (p = 0.054). No significant seasonal predominance was observed for the other specific aetiological agents of CAP. In 58% of the CAP patients who were hospitalized in the autumn we identified a pneumococcal aetiology, whilst this agent was found in only 32% of the cases in the winter. In contrast with popular public opinion, winter with its low temperatures is not the main reason for the development of community-acquired pneumonia. Most of the specific aetiologies for community-acquired pneumonia, with the exception of respiratory viruses and Mycoplasma pneumoniae, have no seasonal predilection.
The role of 11β-hydroxysteroid dehydrogenase in the pathogenesis of hypertension
Authors: S van Uum
Journal: Cardiovascular Research (1998)

The two 11β-hydroxysteroid dehydrogenase (11β-HSD) isozymes catalyze the interconversion of cortisol and cortisone. Type 1 11β-HSD (11β-HSD1) has bidirectional activity, while type 2 11β-HSD (11β-HSD2) mainly converts cortisol into cortisone. Of these two hormones only cortisol has affinity to mineralocorticoid receptors (MRs) and thus induces mineralocorticoid effects. A normal activity of 11β-HSD2 is crucial for prevention of mineralocorticoid activity of cortisol. Absent or decreased 11β-HSD2 activity results in cortisol-mediated hypermineralocorticoid hypertension. In several hypertensive syndromes a decreased 11β-HSD2 activity has been described as the pathogenetic mechanism of the increased blood pressure. In the apparent mineralocorticoid excess (AME) syndrome type 1, absence of 11β-HSD2 activity is caused by mutations in the gene coding for 11β-HSD2. In licorice-induced hypertension glycyrrhetinic acid, the active substituent of licorice, inhibits 11β-HSD2 resulting in an acquired hypermineralocorticoid state. 11β-HSD2 activity is not decreased in glucocorticoid hypertension (Cushing's syndrome). In essential hypertension some evidence for decreased systemic and skin activity of 11β-HSD1 and/or 11β-HSD2 has been found, while renal activity of both isozymes appears to be normal. 11β-HSD2 activity is also present in cardiovascular myocytes of humans and dogs, and inhibition of 11β-HSD potentiates the vascular response to catecholamines. Although MRs in the central nervous system have been incriminated in the pathogenesis of mineralocorticoid hypertension, a pathophysiological role for 11β-HSD2 has not yet been described. Finally, in the placenta 11β-HSD2 reduces fetal exposure to maternal glucocorticoids and a decreased activity of this isozyme may result in low birth weight and increased risk of high blood pressure at adult age.
A Role for TAZ in Migration, Invasion, and Tumorigenesis of Breast Cancer Cells
Authors: Siew Wee Chan, Chun Jye Lim, Ke Guo, Chee Peng Ng, Ian Lee, Walter Hunziker, Qi Zeng, Wanjin Hong
Journal: Cancer Research (2008)

Abstract TAZ (WWTR1), identified as a 14-3-3 binding protein with a PDZ binding motif, modulates mesenchymal stem cell differentiation. We now show that TAZ plays a critical role in the migration, invasion, and tumorigenesis of breast cancer cells. TAZ is conspicuously expressed in human breast cancer cell lines in which its expression levels generally correlate with the invasiveness of cancer cells. Overexpression of TAZ in low-expressing MCF10A cells causes morphologic changes characteristic of cell transformation and promotes cell migration and invasion. Conversely, RNA interference–mediated knockdown of TAZ expression in MCF7 and Hs578T cells reduces cell migration and invasion. TAZ knockdown in MCF7 cells also retards anchorage-independent growth in soft agar and tumorigenesis in nude mice. Significantly, TAZ is overexpressed in ∼20% of breast cancer samples. These results indicate that TAZ plays a role in the migration, invasion, and tumorigenesis of breast cancer cells and thus presents a novel target for the detection and treatment of breast cancer. [Cancer Res 2008;68(8):2592–8]
Measurement of pulmonary arterial distensibility in the dog
Authors: S. R. Reuben, B. J. Gersh, J. P. Swadling, G. d. J. Lee
Journal: Cardiovascular Research (1970)

Journal Article Measurement of pulmonary arterial distensibility in the dog Get access S. R. Reuben, S. R. Reuben From the Cardiac Department and the Nuffield Department of Anaesthetics, Radcliffe Infirmary, Oxford Search for other works by this author on: Oxford Academic PubMed Google Scholar B. J. Gersh, B. J. Gersh From the Cardiac Department and the Nuffield Department of Anaesthetics, Radcliffe Infirmary, Oxford Search for other works by this author on: Oxford Academic PubMed Google Scholar J. P. Swadling, J. P. Swadling From the Cardiac Department and the Nuffield Department of Anaesthetics, Radcliffe Infirmary, Oxford Search for other works by this author on: Oxford Academic PubMed Google Scholar G. de J. Lee G. de J. Lee From the Cardiac Department and the Nuffield Department of Anaesthetics, Radcliffe Infirmary, Oxford Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 4, Issue 4, October 1970, Pages 473–481, https://doi.org/10.1093/cvr/4.4.473 Published: 01 October 1970 Article history Accepted: 16 January 1970 Published: 01 October 1970
Excavating Past Population Structures by Surname-Based Sampling: The Genetic Legacy of the Vikings in Northwest England
Authors: G. R. Bowden, P. Balaresque, T. E. King, Z. Hansen, A. C. Lee, G. Pergl-Wilson, E. Hurley, S. J. Roberts, P. Waite, J. Jesch, A. L. Jones, M. G. Thomas, S. E. Harding, M. A. Jobling
Journal: Molecular Biology and Evolution (2007)

The genetic structures of past human populations are obscured by recent migrations and expansions and have been observed only indirectly by inference from modern samples. However, the unique link between a heritable cultural marker, the patrilineal surname, and a genetic marker, the Y chromosome, provides a means to target sets of modern individuals that might resemble populations at the time of surname establishment. As a test case, we studied samples from the Wirral Peninsula and West Lancashire, in northwest England. Place-names and archaeology show clear evidence of a past Viking presence, but heavy immigration and population growth since the industrial revolution are likely to have weakened the genetic signal of a 1,000-year-old Scandinavian contribution. Samples ascertained on the basis of 2 generations of residence were compared with independent samples based on known ancestry in the region plus the possession of a surname known from historical records to have been present there in medieval times. The Y-chromosomal haplotypes of these 2 sets of samples are significantly different, and in admixture analyses, the surname-ascertained samples show markedly greater Scandinavian ancestry proportions, supporting the idea that northwest England was once heavily populated by Scandinavian settlers. The method of historical surname-based ascertainment promises to allow investigation of the influence of migration and drift over the last few centuries in changing the population structure of Britain and will have general utility in other regions where surnames are patrilineal and suitable historical records survive.