tbuckley/cabot-search huggingface dataset:
A Genome-Wide Screen Reveals Functional Gene Clusters in the Cancer Genome and Identifies EphA2 as a Mitogen in Glioblastoma
Authors: Fenghua Liu, Peter J. Park, Weil Lai, Elizabeth Maher, Arnab Chakravarti, Laura Durso, Xiuli Jiang, Yi Yu, Amanda Brosius, Meredith Thomas, Lynda Chin, Cameron Brennan, Ronald A. DePinho, Isaac Kohane, Rona S. Carroll, Peter M. Black, Mark D. Johnson
Journal: Cancer Research (2006)

A novel genome-wide screen that combines patient outcome analysis with array comparative genomic hybridization and mRNA expression profiling was developed to identify genes with copy number alterations, aberrant mRNA expression, and relevance to survival in glioblastoma. The method led to the discovery of physical gene clusters within the cancer genome with boundaries defined by physical proximity, correlated mRNA expression patterns, and survival relatedness. These boundaries delineate a novel genomic interval called the functional common region (FCR). Many FCRs contained genes of high biological relevance to cancer and were used to pinpoint functionally significant DNA alterations that were too small or infrequent to be reliably identified using standard algorithms. One such FCR contained the EphA2 receptor tyrosine kinase. Validation experiments showed that EphA2 mRNA overexpression correlated inversely with patient survival in a panel of 21 glioblastomas, and ligand-mediated EphA2 receptor activation increased glioblastoma proliferation and tumor growth via a mitogen-activated protein kinase-dependent pathway. This novel genome-wide approach greatly expanded the list of target genes in glioblastoma and represents a powerful new strategy to identify the upstream determinants of tumor phenotype in a range of human cancers.
A Human Immunoglobulin (Ig)A Cα3 Domain Motif Directs Polymeric Ig Receptor–mediated Secretion
Authors: J. Mark Hexham, Kendra D. White, Leonidas N. Carayannopoulos, Wlodeck Mandecki, Renee Brisette, Yih-Sheng Yang, J. Donald Capra
Journal: The Journal of Experimental Medicine (1999)

Polymeric immunoglobulins provide immunological protection at mucosal surfaces to which they are specifically transported by the polymeric immunoglobulin receptor (pIgR). Using a panel of human IgA1/IgG1 constant region "domain swap" mutants, the binding site for the pIgR on dimeric IgA (dIgA) was localized to the Calpha3 domain. Selection of random peptides for pIgR binding and comparison with the IgA sequence suggested amino acids 402-410 (QEPSQGTTT), in a predicted exposed loop of the Calpha3 domain, as a potential binding site. Alanine substitution of two groups of amino acids in this area abrogated the binding of dIgA to pIgR, whereas adjacent substitutions in a beta-strand immediately NH2-terminal to this loop had no effect. All pIgR binding IgA sequences contain a conserved three amino acid insertion, not present in IgG, at this position. These data localize the pIgR binding site on dimeric human IgA to this loop structure in the Calpha3 domain, which directs mucosal secretion of polymeric antibodies. We propose that it may be possible to use a pIgR binding motif to deliver antigen-specific dIgA and small-molecule drugs to mucosal epithelia for therapy.
Ebstein's Anomaly of the Tricuspid Valve
Authors: MARY ALLEN ENGLE, TORRENCE P. B. PAYNE, CAROLINE BRUINS, HELEN B. TAUSSIG
Journal: Circulation (1950)

In Ebstein's anomaly the tricuspid valve is displaced downward so that the upper portion of the right ventricle is incorporated in the right auricle. This imipairs the efficiency of the right side of the heart and produces a distinctive syndrome, which is described here for the first time. Diagnosis is important because this malformation, which is not amenable to surgery, may be confused with the tetralogy of Fallot.
B<scp>IOTIN IN</scp>M<scp>ETABOLISM AND</scp>M<scp>OLECULAR</scp>B<scp>IOLOGY</scp>
Authors: Robert J. McMahon
Journal: Annual Review of Nutrition (2002)

▪ Abstract Biotin is a water-soluble vitamin required by all organisms by virtue of its essential role in carboxylation reactions. Although the metabolism and role of biotin in intermediary metabolism are well established, biotin remains one of the most poorly understood water-soluble vitamins in terms of nutritional requirements and responsiveness to physiological and pharmacological states. Significant advances in the understanding of biotin nutriture have been recently accomplished through the description of the kinetics and regulation of biotin transport and improved methods for biotin status assessment. Additionally, the potential role of biotin in the regulation of gene expression has been strengthened through description of altered gene expression during biotin deficiency and through newly described enzymatic activities of the enzyme biotinidase. Given mounting evidence of suboptimum biotin status, a more complete understanding of these aspects of biotin should lead to a greater appreciation of the ways in which biotin aids in the maintenance of health.
Treatment of hyponatraemic seizures with intravenous 29{middle dot}2% saline
Authors: G. Gill
Journal: BMJ (1986)

<h3>ABSTRACT</h3> <i>Toxoplasma gondii</i> is a eukaryotic parasite that form latent cyst in the brain of immunocompetent individuals. The latent parasites infection of the immune privileged central nervous system is linked to most complications. With no drug currently available to eliminate the latent cysts in the brain of infected hosts, the consequences of neurons long-term infection are unknown. It has long been known that <i>T. gondii</i> specifically differentiate into a latent form (bradyzoite) in neurons, but how the infected neuron is responding to the infection remain to be elucidated. We have established a new in vitro model resulting in the production of fully mature bradyzoites cysts in brain cells. Using dual, host and parasite, RNA-seq we characterized the dynamics of differentiation of the parasite, revealing the involvement of key pathways in this process. Moreover, we identified how the infected brain cells responded to the parasite infection revealing the drastic changes that take place. We showed that neuronal specific pathways are strongly affected, with synapse signaling being particularly affected, especially glutamatergic synapse. The establishment of this new <i>in vitro</i> model allows to investigate both the dynamics of the parasite differentiation and the specific response of neurons to the long term infection by this parasite.
A Spotlight from Prostate Cancer
Authors: Harvey R. Herschman, Johannes Czernin
Journal: Cancer Discovery (2012)

Abstract Serum prostate-specific antigen (PSA) levels are used to monitor the development of prostate cancer, recurrence after surgery, and response to subsequent therapy. However, the clinical implications often are difficult to interpret. Ulmert and colleagues report use of a positron-emitting labeled monoclonal antibody directed to a unique PSA epitope to noninvasively image PSA-positive prostate cancer xenografts and to measure both androgen-stimulated PSA expression and androgen therapy-responsive PSA decreases. Cancer Discov; 2(4); 301–3. ©2012 AACR. Commentary on Ulmert et al., p. 320.
Novel gp91 <sup> <i>phox</i> </sup> Homologues in Vascular Smooth Muscle Cells
Authors: Bernard Lassègue, Dan Sorescu, Katalin Szöcs, QiQin Yin, Marjorie Akers, Yong Zhang, Sharon L. Grant, J. David Lambeth, Kathy K. Griendling
Journal: Circulation Research (2001)

Abstract —Emerging evidence indicates that reactive oxygen species are important regulators of vascular function. Although NAD(P)H oxidases have been implicated as major sources of superoxide in the vessel wall, the molecular identity of these proteins remains unclear. We recently cloned nox1 (formerly mox-1), a member of a new family of gp91 phox homologues, and showed that it is expressed in proliferating vascular smooth muscle cells (VSMCs). In this study, we examined the expression of three nox family members, nox1, nox4, and gp91 phox , in VSMCs, their regulation by angiotensin II (Ang II), and their role in redox-sensitive signaling. We found that both nox1 and nox4 are expressed to a much higher degree than gp91 phox in VSMCs. Although serum, platelet-derived growth factor (PDGF), and Ang II downregulated nox4, they markedly upregulated nox1, suggesting that this enzyme may account for the delayed phase of superoxide production in these cells. Furthermore, an adenovirus expressing antisense nox1 mRNA completely inhibited the early phase of superoxide production induced by Ang II or PDGF and significantly decreased activation of the redox-sensitive signaling molecules p38 mitogen-activated protein kinase and Akt by Ang II. In contrast, redox-independent pathways induced by PDGF or Ang II were unaffected. These data support a role for nox1 in redox signaling in VSMCs and provide insight into the molecular identity of the VSMC NAD(P)H oxidase and its potentially critical role in vascular disease.
Supraphysiological androgen levels induce cellular senescence in human prostate cancer cells through the Src-Akt pathway
Authors: Julia Roediger, Wiebke Hessenkemper, Sophie Bartsch, Marina Manvelyan, Soeren S Huettner, Thomas Liehr, Mohsen Esmaeili, Susan Foller, Iver Petersen, Marc-Oliver Grimm, Aria Baniahmad
Journal: Molecular Cancer (2014)

Prostate cancer (PCa) is the second leading cause of cancer mortality of men in Western countries. The androgen receptor (AR) and AR-agonists (androgens) are required for the development and progression of the normal prostate as well as PCa. However, it is discussed that in addition to their tumor promoting activity, androgens may also exhibit tumor suppressive effects. A biphasic growth response to androgens a growth-promoting and -inhibition has been observed that suggests that administration of supraphysiological androgen levels mediates growth reduction in AR expressing PCa cells. Detection of senescence markers, three dimensional interphase fluorescence in situ hybridization (3D-iFISH), qRT-PCR, Western blotting, detection of GFP fusions, prostatectomy, ex vivo culturing. Here, we describe that supraphysiological levels of androgens induce cell cycle arrest and markers of cellular senescence in human PCa cells, which may in part explain the growth inhibitory role of androgens. The expression of the senescence associated beta galactosidase is observed by treatment with the natural androgen DHT or the less metabolized synthetic androgen R1881. The induction of senescence marker was detected in human PCa cell lines as well as in human primary PCa tissue derived from prostatectomy treated ex vivo. Using interphase FISH (iFISH) suggests that the androgen-induced cellular senescence is associated with localizing the genomic E2F1 locus to senescence associated heterochromatic foci. Analysis of different signaling pathways in LNCaP cells suggest that the p16-Rb-E2F1 pathway is essential for the induction of cellular senescence since treatment with siRNA directed against p16 reduces the level of androgen-induced cellular senescence. Based on the rapid induction of androgen-mediated cellular senescence we identified the Src-PI3K-Akt-signaling pathway and autophagy being in part involved in androgen regulation. Taken together, our data suggest that AR-agonists at supraphysiological levels mediate induction of cellular senescence in human PCa cells, which may have a protective anti-cancer role. These results provide also new insights for understanding androgen-mediated regulation of PCa growth.
A Phase I/II Study of Erlotinib in Combination with the Anti-Insulin-Like Growth Factor-1 Receptor Monoclonal Antibody IMC-A12 (Cixutumumab) in Patients with Advanced Non-small Cell Lung Cancer
Authors: Andrew Weickhardt, Robert Doebele, Ana Oton, Janice Lettieri, DeLee Maxson, Michele Reynolds, Amy Brown, Mary K. Jackson, Grace Dy, Araba Adjei, Gerald Fetterly, Xian Lu, Wilbur Franklin, Marileila Varella-Garcia, Fred R. Hirsch, Murry W. Wynes, Hagop Youssoufian, Alex Adjei, D. Ross Camidge
Journal: Journal of Thoracic Oncology (2012)
Long-Term Follow-Up of Patients With Mild Coronary Artery Disease and Endothelial Dysfunction
Authors: Jassim Al Suwaidi, Shuichi Hamasaki, Stuart T. Higano, Rick A. Nishimura, David R. Holmes, Amir Lerman
Journal: Circulation (2000)

Background —Coronary endothelial dysfunction is characterized by vasoconstrictive response to the endothelium-dependent vasodilator acetylcholine. Although endothelial dysfunction is considered an early phase of coronary atherosclerosis, there is a paucity of information regarding the outcome of these patients. Thus, this study was designed to evaluate the outcome of patients with mild coronary artery disease on the basis of their endothelial function. Methods and Results —Follow-up was obtained in 157 patients with mildly diseased coronary arteries who had undergone coronary vascular reactivity evaluation by graded administration of intracoronary acetylcholine, adenosine, and nitroglycerin and intracoronary ultrasound at the time of diagnostic study. Patients were divided on the basis of their response to acetylcholine into 3 groups: group 1 (n=83), patients with normal endothelial function; group 2 (n=32), patients with mild endothelial dysfunction; and group 3 (n=42), patients with severe endothelial dysfunction. Over an average 28-month follow-up (range, 11 to 52 months), none of the patients from group 1 or 2 had cardiac events. However, 6 (14%) with severe endothelial dysfunction had 10 cardiac events ( P &lt;0.05 versus groups 1 and 2). Cardiac events included myocardial infarction, percutaneous or surgical coronary revascularization, and/or cardiac death. Conclusions —Severe endothelial dysfunction in the absence of obstructive coronary artery disease is associated with increased cardiac events. This study supports the concept that coronary endothelial dysfunction may play a role in the progression of coronary atherosclerosis.
ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice
Authors: Andrew J. Murphy, Mani Akhtari, Sonia Tolani, Tamara Pagler, Nora Bijl, Chao-Ling Kuo, Mi Wang, Marie Sanson, Sandra Abramowicz, Carrie Welch, Andrea E. Bochem, Jan Albert Kuivenhoven, Laurent Yvan-Charvet, Alan R. Tall
Journal: Journal of Clinical Investigation (2011)

Leukocytosis is associated with increased cardiovascular disease risk in humans and develops in hypercholesterolemic atherosclerotic animal models. Leukocytosis is associated with the proliferation of hematopoietic stem and multipotential progenitor cells (HSPCs) in mice with deficiencies of the cholesterol efflux-promoting ABC transporters ABCA1 and ABCG1 in BM cells. Here, we have determined the role of endogenous apolipoprotein-mediated cholesterol efflux pathways in these processes. In Apoe⁻/⁻ mice fed a chow or Western- type diet, monocytosis and neutrophilia developed in association with the proliferation and expansion of HSPCs in the BM. In contrast, Apoa1⁻/⁻ mice showed no monocytosis compared with controls. ApoE was found on the surface of HSPCs, in a proteoglycan-bound pool, where it acted in an ABCA1- and ABCG1-dependent fashion to decrease cell proliferation. Accordingly, competitive BM transplantation experiments showed that ApoE acted cell autonomously to control HSPC proliferation, monocytosis, neutrophilia, and monocyte accumulation in atherosclerotic lesions. Infusion of reconstituted HDL and LXR activator treatment each reduced HSPC proliferation and monocytosis in Apoe⁻/⁻ mice. These studies suggest a specific role for proteoglycanbound ApoE at the surface of HSPCs to promote cholesterol efflux via ABCA1/ABCG1 and decrease cell proliferation, monocytosis, and atherosclerosis. Although endogenous apoA-I was ineffective, pharmacologic approaches to increasing cholesterol efflux suppressed stem cell proliferative responses.
Response to Letters Regarding Article, “Comparison Between Transcatheter and Surgical Prosthetic Valve Implantation in Patients With Severe Aortic Stenosis and Reduced Left Ventricular Ejection Fraction”
Authors: M.A. Clavel, J.G. Webb, J. Rodés-Cabau, J.B. Masson, E. Dumont, R. De Larochellière, D. Doyle, S. Bergeron, H. Baumgartner, I.G. Burwash, J.G. Dumesnil, G. Mundigler, R. Moss, A. Kempny, R. Bagur, J. Bergler-Klein, R. Gurvitch, P. Mathieu, P. Pibarot
Journal: Circulation (2011)
Biliary drainage for obstructive jaundice enhances hepatic energy status in humans: a 31-phosphorus magnetic resonance spectroscopy study
Authors: D V Mann
Journal: Gut (2002)

Background: Biliary obstruction impairs liver function although the pathophysiological mechanism is incompletely understood. Aims: The aim of this study was to examine serial changes in liver metabolism in patients with obstructive jaundice using image guided in vivo 31-phosphorus magnetic resonance spectroscopy (31P MRS). This technique allows repeated and non-invasive assay of organ energy metabolism and phospholipid biochemistry. Patients: We studied 10 patients presenting with obstructive jaundice secondary to extrahepatic localised malignancy. There were eight men and two women, median age 72 years (range 54–94), six with cholangiocarcinoma (all Bismuth type 1) and four with carcinoma of the head of the pancreas. Ten healthy volunteers (median age 24 years (range 21–26)) were studied for comparison. Methods: Hepatic metabolism in jaundiced patients was measured by 31P MRS at presentation and again after a one week period of biliary drainage. Conventional liver function tests were also recorded. Results: Compared with controls, liver spectra from jaundiced patients contained an excess of phosphomonoester (PME) metabolites (PME/total phosphate median 10.3% (interquartile range 8.7–11.5) in controls, 15.4% (13.1–17.7) in jaundiced cases; p<0.01). Biliary decompression was achieved in all patients (five with internal stents and five by external drainage catheters), and plasma biochemistry improved predictably (bilirubin 176 μmol/l (158–351) at presentation, 110 μmol/l (42–241) after drainage for one week; p<0.01). Enhancement of hepatic energy status, measured by the ratio of adenosine triphosphate (ATP) to inorganic phosphate (Pi), was observed in all cases after relief of biliary obstruction (ATP/Pi 1.4 (1.17–1.69) at presentation, 1.97 (1.4–2.48) after drainage; p<0.01) and was independent of the route of bile drainage. Hepatic phosphodiester (PDE) content was decreased after relief of obstruction (PDE/total phosphate 25.2% (20.5–27.4) at presentation, 19.8% (16.6–24.5) after drainage; p<0.01). This change was probably due to a reduction in the contribution from bile contents to this resonance as a strong PDE signal was also detectable in spectra obtained from separate bile specimens. Conclusions: Obstructive jaundice produces alterations in liver phosphoester biochemistry, most likely reflecting disturbances in phospholipid metabolism. Relief of biliary obstruction is associated with a measurable increase in hepatic energy status. Bile may contribute to the phosphodiester signal of the 31-phosphorus liver spectrum and changes in these resonances must therefore be interpreted with caution and in relation to the clinical situation. Monitoring of liver metabolism by 31P MRS may allow clinicians to refine the selection and timing of therapeutic options in jaundiced patients.
Painful gynecomastia following cytotoxic therapy for testis cancer: a potentially favorable prognostic sign?
Authors: D L Trump, S A Anderson
Journal: Journal of Clinical Oncology (1983)

Ninety-six patients who received cytotoxic chemotherapy for germ cell neoplasms of the testis were studied. Painful gynecomastia developed in eight patients (8%) between 6 and 24 weeks after the initiation of cytotoxic therapy (mean 18 wk). Serum content of the beta subunit of human chorionic gonadotropin was normal in each patient when gynecomastia developed. Gynecomastia occurred following cytotoxic therapy for advanced disease in seven patients, and one patient was receiving adjunctive drug therapy for stage I disease. Six of the seven patients with advanced disease were in complete remission when gynecomastia developed; survival was superior in patients who developed treatment-related gynecomastia compared to those patients who did not (p less than 0.05). Gynecomastia may occur in adult males after cytotoxic therapy for testis cancer; such gynecomastia does not necessarily indicate recurrent malignancy and may be a favorable prognostic sign.
Calcium polymorphic ventricular tachycardia: a new name for CPVT?
Authors: F. Brette
Journal: Cardiovascular Research (2010)

This editorial refers to ‘Na+-dependent SR Ca2+ overload induces arrhythmogenic events in mouse ardiomyocytes with a human CPVT mutation’ by S. Sedej et al ., pp. 50–59, this issue. 

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by adrenergically mediated ventricular tachyarrhythmia leading to syncope and sudden cardiac death.1 Patients with CPVT show ventricular tachycardia during exercise or emotional stress in the absence of any structural heart disease. Also, any increase in the levels of circulating catecholamines (during stress or exercise, i.e. β-adrenergic stimulation) leads to a bi-directional ventricular tachycardia. Since 2001, more than 70 mutations in either ryanodine receptors (RyR) or an RyR-associated protein [calsequestrin, involved in sarcoplasmic reticulum (SR) Ca2+ buffering] have been identified in CPVT families.2,3 During the last several years, the physiological consequences of such mutations have been mainly investigated in expression systems (e.g. HEK cells expressing mutant RyR).4,5 However, expression systems lack a cardiac intracellular environment (accessory proteins, cell structure, etc.), hampering a complete understanding of how such mutations induce cardiac arrhythmias in native cardiac myocytes. The development of the first knock-in mouse model of human CPVT (mutation in RyR at position R4496C) by Priori's group2 shows that the mouse phenotype has striking similarity with the clinical human CPVT symptoms. Since then, it has been possible to investigate the effect of …
Clinical determinants and chronotrophic responses of maximal exercise capacity in patients with early stage of sarcoidosis
Authors: Muserrefe Nur Karadalli, Meral Bosnak Guclu, Burcu Camcioglu, Zeynep Aribas, Gülsah Bargi, Nurdan Koktürk, Haluk Turktas
Journal: European Respiratory Journal (2014)

Background: Patients with early stage of sarcoidosis have reduced exercise capacity however; studies investigating the determinants of maximal exercise capacity and patients9 chronotropic responses to maximal exercise are limited.  Aim: To investigate the clinical determinants and chronotrophic responses of Modified incremental shuttle walk test (ISWT) in patients with early stage of sarcoidosis.  Methods: Thirty-four patients with sarcoidosis (46.58±10.30 years) were included. Pulmonary functions were measured. Maximal exercise capacity was evaluated using Modified ISWT, respiratory muscle strength (MIP, MEP) using a mouth pressure device, peripheral muscle strength using dynamometer, dyspnea using Modified Medical Research Council (MMRC) dyspnea scale and fatigue using Fatigue Severity Scale (FSS).  Results: There were statistically significant correlations between Modified ISWT distance and age, shoulder flexor, quadriceps strength, MlP, MEP, dyspnea and fatigue perception (p  Conclusion: Upper extremity muscle strength and fatigue are factors significantly contributing to impaired maximal exercise capacity, and chronotropic incompetence is prevalent in patients with sarcoidosis. Maximal exercise capacity worsens with decreasing peripheral and respiratory muscle strength. The effects of exercise training on maximal exercise capacity and chronotrophic response should be investigated.