tbuckley/cabot-search huggingface dataset:
Huntingtin Interacting Protein 1 Is a Novel Brain Tumor Marker that Associates with Epidermal Growth Factor Receptor
Authors: Sarah V. Bradley, Eric C. Holland, Grace Y. Liu, Dafydd Thomas, Teresa S. Hyun, Theodora S. Ross
Journal: Cancer Research (2007)

Abstract Huntingtin interacting protein 1 (HIP1) is a multidomain oncoprotein whose expression correlates with increased epidermal growth factor receptor (EGFR) levels in certain tumors. For example, HIP1-transformed fibroblasts and HIP1-positive breast cancers have elevated EGFR protein levels. The combined association of HIP1 with huntingtin, the protein that is mutated in Huntington's disease, and the known overexpression of EGFR in glial brain tumors prompted us to explore HIP1 expression in a group of patients with different types of brain cancer. We report here that HIP1 is overexpressed with high frequency in brain cancers and that this overexpression correlates with EGFR and platelet-derived growth factor β receptor expression. Furthermore, serum samples from patients with brain cancer contained anti-HIP1 antibodies more frequently than age-matched brain cancer–free controls. Finally, we report that HIP1 physically associates with EGFR and that this association is independent of the lipid, clathrin, and actin interacting domains of HIP1. These findings suggest that HIP1 may up-regulate or maintain EGFR overexpression in primary brain tumors by directly interacting with the receptor. This novel HIP1-EGFR interaction may work with or independent of HIP1 modulation of EGFR degradation via clathrin-mediated membrane trafficking pathways. Further investigation of HIP1 function in brain cancer biology and validation of its use as a prognostic or predictive brain tumor marker are now warranted. [Cancer Res 2007;67(8):3609–15]
Meningiomas May Be a Component Tumor of Multiple Endocrine Neoplasia Type 1
Authors: Behnam Asgharian, Yuan-Jia Chen, Nicholas J. Patronas, Paolo L. Peghini, James C. Reynolds, Alexander Vortmeyer, Zhengping Zhuang, David J. Venzon, Fathia Gibril, Robert T. Jensen
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Recently, an increased incidence of some nonendocrine tumors are reported in patients with multiple endocrine neoplasia type 1 (MEN 1). There are rare reports of meningiomas and other central nervous system tumors in these patients, but it is unknown if they are more frequent or if allelic loss of the MEN1 gene is important in their pathogenesis. The aim of this study was to address these two latter questions. Experimental Design: Results from a prospective study of 74 MEN 1 patients with suspected/proven pancreatic endocrine tumors (PETs) were analyzed, as well as molecular studies performed on a resected meningioma. All patients had serial brain imaging studies (computed tomography, magnetic resonance imaging, and octreoscanning since 1994) and yearly studies evaluating MEN 1 involvement with a mean follow-up of 7.2 years. Results were compared with 185 patients with sporadic Zollinger-Ellison syndrome. Results: Six patients (8%) had meningiomas. Meningiomas were single and found late in the MEN 1 course (mean age = 51 years). Magnetic resonance imaging/computed tomography were more sensitive than octreoscanning. Their diagnosis averaged 18 years after the onset of hyperparathyroidism, 10–15 years after pituitary disease or PETs. Meningiomas were 11 times more frequent in patients with PETs with MEN 1 than without MEN 1 (P = 0.017). No clinical, laboratory, or MEN 1 feature distinguished patients with meningiomas. Meningiomas were asymptomatic and 60% showed no growth. A resected meningioma showed loss of heterozygosity at 11q13 and 1p, including at p73 and ARHI/NOEY2 locus, but not at the neurofibromatosis 2 gene locus. Conclusions: These results show meningiomas are not an infrequent occurrence in MEN 1, and loss of the function of the MEN1 gene product plays a role in their pathogenesis in these patients.
Sildenafil (Viagra) Prolongs Cardiac Repolarization by Blocking the Rapid Component of the Delayed Rectifier Potassium Current
Authors: Peter Geelen, Benoit Drolet, Jimmy Rail, Jocelyn Bérubé, Pascal Daleau, Guy Rousseau, René Cardinal, Gilles E. O’Hara, Jacques Turgeon
Journal: Circulation (2000)

Background —Several cases of unexpected death have been reported with sildenafil in patients predisposed to ischemic cardiac events. Although acute episodes of ischemia could account for some of these deaths, we hypothesized that sildenafil may have unsuspected electrophysiological effects predisposing some patients to proarrhythmia. Methods and Results —Studies were undertaken in 10 isolated guinea pig hearts that demonstrated prolongation of cardiac repolarization in a reverse use-dependent manner by sildenafil 30 μmol/L. Action potential duration increased 15% from baseline 117±3 to 134±2 ms with sildenafil during pacing at 250 ms cycle length, whereas a 6% increase from 99±2 to 105±2 ms was seen with pacing at 150 ms cycle length. Experiments in human ether-a-go-go –related gene (HERG)–transfected HEK293 cells (n=30) demonstrated concentration-dependent block of the rapid component (I Kr ) of the delayed rectifier potassium current: activating current was 50% decreased at 100 μmol/L. This effect was confirmed using HERG-transfected Chinese hamster ovary (CHO) cells, which exhibit no endogenous I K -like current. Conclusions —Sildenafil possesses direct cardiac electrophysiological effects similar to class III antiarrhythmic drugs. These effects are observed at concentrations that may be found in conditions of impaired drug elimination such as renal or hepatic insufficiency, during coadministration of another CYP3A substrate/inhibitor, or after drug overdose and offer a new potential explanation for sudden death during sildenafil treatment.
The Big Idea: the coxib crisis Iron, aspirin and heart disease risk revisited
Authors: J. L Sullivan
Journal: Journal of the Royal Society of Medicine (2007)

Kuhn1 used the term ‘crisis’ for the chaotic situation provoked by an unresolved anomaly (i.e. a finding not explainable by a prevailing scientific paradigm). As a crisis evolves, the rules by which the old paradigm are applied to new findings become increasingly blurred. Kuhn's description of a paradigm in crisis1 applies accurately to recent discussions of the cardiovascular risks of the coxibs.2,3 Recognition of paradigm crises is problematic in all scientific fields; however, in medical science, failure to recognize and resolve an ongoing crisis can put lives at risk by delaying a necessary paradigm shift.

There had been a ‘working paradigm’, reviewed by Antman et al.2 in a paper that aptly presents the current crisis. Their account of the ‘tsunami of events’ following withdrawal of rofecoxib in 2004 suggests an ongoing paradigm crisis. By the early 1990s, the prevailing paradigm involved ‘the recognition that there are two different cyclooxygenases (COXs), which ‘led to the straightforward view that COX-2 is responsible for the adverse pro-inflammatory effects of prostanoids and that non-specific COX inhibitors cause bleeding by inhibiting COX-1 in platelets’.2 The paradigm encouraged development of COX-2 selective inhibitors to isolate an assumed anti-inflammatory mechanism of aspirin from the mechanism causing haemorrhage.

Which of the direct and indirect effects of long-term aspirin use is responsible for cardioprotection remains fundamentally a matter of speculation. There is no reliable proof that the mechanisms under most intense discussion are responsible for prevention of coronary events with regular use. The ‘working paradigm’2 has been overtaken by a paradigm crisis. The mechanism of benefit could be an unexpected effect of aspirin or it could be hidden within one of the known harmful effects of aspirin.
A Phase I Trial of the Novel Farnesyl Protein Transferase Inhibitor, BMS-214662, in Combination with Paclitaxel and Carboplatin in Patients with Advanced Cancer
Authors: Grace K. Dy, Laura M. Bruzek, Gary A. Croghan, Sumithra Mandrekar, Charles Erlichman, Prema Peethambaram, Henry C. Pitot, Lorelei J. Hanson, Joel M. Reid, Alfred Furth, Shinta Cheng, Robert E. Martell, Scott H. Kaufmann, Alex A. Adjei
Journal: Clinical Cancer Research (2005)

Abstract Purpose: This phase I study was conducted to determine the toxicities, pharmacokinetics, and pharmacodynamics of BMS-214662, a farnesyl transferase inhibitor, in combination with paclitaxel and carboplatin, in patients with advanced solid tumors. Experimental Design: Patients with solid tumors received one of six escalating dose levels of BMS-214662 infused over 1 hour given following paclitaxel and carboplatin on the first day of a 21-day cycle. Toxicities were graded by the National Cancer Institute common toxicity criteria and recorded as maximum grade per patient for each treatment cycle. Inhibition of farnesyl transferase activity in peripheral blood mononuclear cells (PBMCs) was evaluated. Accumulation of unfarnesylated HDJ-2 in PBMCs of patients was evaluated as a marker of farnesyl transferase inhibition by BMS-214662. Results: Thirty patients received 141 cycles of treatment through six dose levels. Dose-limiting toxicities were neutropenia, thrombocytopenia, nausea, and vomiting. There was no pharmacokinetic interaction between BMS-214662 and paclitaxel. The maximum tolerated dose was established as BMS-214662 (160 mg/m2), paclitaxel (225 mg/m2) and carboplatin (area under the curve = 6 on day 1), every 21 days. Inhibition of HDJ-2 farnesylation in PBMCs of patients was shown. One measurable partial response was observed in a patient with taxane-resistant esophageal cancer. There was partial regression of evaluable disease in two other patients (endometrial and ovarian cancer). Stable disease (&amp;gt; 4 cycles) occurred in eight other patients. Conclusions: The combination of BMS-214662 with paclitaxel and carboplatin was well tolerated, with broad activity in solid tumors. There was no correlation between dose level and accumulation of unfarnesylated HDJ-2 in PBMCs nor tumor response.
Anti-thrombotic effects of a nitric oxide-releasing, gastric-sparing aspirin derivative.
Authors: J L Wallace, W McKnight, P Del Soldato, A R Baydoun, G Cirino
Journal: Journal of Clinical Investigation (1995)

Effects of a nitroxybutylester derivative of aspirin (NCX 4215) on platelet aggregation and prostanoid synthesis were compared to the effects of aspirin. NCX 4215 was approximately seven times more potent than aspirin as an inhibitor of thrombin-induced human platelet aggregation in vitro, but did not inhibit platelet thromboxane synthesis or gastric prostaglandin synthesis. NCX 4215 released nitric oxide when incubated in the presence of platelets and increased platelet levels of cGMP within 10 min of exposure, while aspirin did not. The anti-aggregatory effects of NCX 4215 in vitro were significantly attenuated by 10 microM hemoglobin. In ex vivo studies of ADP- or collagen- or thrombin-induced rat platelet aggregation, aspirin and NCX 4215 had comparable inhibitory effects 3 h after administration. Aspirin (10-120 mg/kg) caused extensive hemorrhagic erosion formation in the stomach of the rat within 3 h of oral administration, while NCX 4215 did not produce significant damage at doses of up to 300 mg/kg, nor when given daily for two weeks at 166 mg/kg. NCX 4215 did not alter systemic arterial blood pressure when administered intravenously to the rat. These studies demonstrate that NCX 4215 has comparable or enhanced anti-thrombotic activity to that of aspirin, but does not cause gastric damage or alter systemic blood pressure. The anti-thrombotic actions of NCX 4215 are, at least in part, due to generation of nitric oxide.
Prostate tumor OVerexpressed-1 (PTOV1) down-regulates HES1 and HEY1 notch targets genes and promotes prostate cancer progression
Authors: Lide Alaña, Marta Sesé, Verónica Cánovas, Yolanda Punyal, Yolanda Fernández, Ibane Abasolo, Inés de Torres, Cristina Ruiz, Lluís Espinosa, Anna Bigas, Santiago Ramón y Cajal, Pedro L Fernández, Florenci Serras, Montserrat Corominas, Timothy M Thomson, Rosanna Paciucci
Journal: Molecular Cancer (2014)

PTOV1 is an adaptor protein with functions in diverse processes, including gene transcription and protein translation, whose overexpression is associated with a higher proliferation index and tumor grade in prostate cancer (PC) and other neoplasms. Here we report its interaction with the Notch pathway and its involvement in PC progression. Stable PTOV1 knockdown or overexpression were performed by lentiviral transduction. Protein interactions were analyzed by co-immunoprecipitation, pull-down and/or immunofluorescence. Endogenous gene expression was analyzed by real time RT-PCR and/or Western blotting. Exogenous promoter activities were studied by luciferase assays. Gene promoter interactions were analyzed by chromatin immunoprecipitation assays (ChIP). In vivo studies were performed in the Drosophila melanogaster wing, the SCID-Beige mouse model, and human prostate cancer tissues and metastasis. The Excel package was used for statistical analysis. Knockdown of PTOV1 in prostate epithelial cells and HaCaT skin keratinocytes caused the upregulation, and overexpression of PTOV1 the downregulation, of the Notch target genes HEY1 and HES1, suggesting that PTOV1 counteracts Notch signaling. Under conditions of inactive Notch signaling, endogenous PTOV1 associated with the HEY1 and HES1 promoters, together with components of the Notch repressor complex. Conversely, expression of active Notch1 provoked the dismissal of PTOV1 from these promoters. The antagonist role of PTOV1 on Notch activity was corroborated in the Drosophila melanogaster wing, where human PTOV1 exacerbated Notch deletion mutant phenotypes and suppressed the effects of constitutively active Notch. PTOV1 was required for optimal in vitro invasiveness and anchorage-independent growth of PC-3 cells, activities counteracted by Notch, and for their efficient growth and metastatic spread in vivo. In prostate tumors, the overexpression of PTOV1 was associated with decreased expression of HEY1 and HES1, and this correlation was significant in metastatic lesions. High levels of the adaptor protein PTOV1 counteract the transcriptional activity of Notch. Our evidences link the pro-oncogenic and pro-metastatic effects of PTOV1 in prostate cancer to its inhibitory activity on Notch signaling and are supportive of a tumor suppressor role of Notch in prostate cancer progression.
HIV-induced immune deficiency is associated with a higher risk of hepatocarcinoma, ANRS CO3 Aquitaine Cohort, France, 1998–2008
Authors: Mathias Bruyand, François Dabis, Marie-Anne Vandenhende, Estibaliz Lazaro, Didier Neau, Olivier Leleux, Stéphane Geffard, Philippe Morlat, Geneviève Chêne, Fabrice Bonnet
Journal: Journal of Hepatology (2011)
Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia
Authors: Mario Cazzola, Rosangela Invernizzi, Gaetano Bergamaschi, Sonia Levi, Barbara Corsi, Erica Travaglino, Valeria Rolandi, Giorgio Biasiotto, Jim Drysdale, Paolo Arosio
Journal: Blood (2003)
Elective Countershock in Unanesthetized Patients with Use of an Esophageal Electrode
Authors: E. M. MCNALLY, E. C. MEYER, R. LANGENDORF
Journal: Circulation (1966)

A new electrode arrangement for the administration of elective direct-current countershock was studied, in which one electrode was placed in the esophagus, adjacent to the heart, and the other on the precordium. Thirteen patients with chronic atrial fibrillation were converted to sinus rhythm by the esophageal technic. Though the majority were, on clinical grounds, difficult cases for conversion, 11 were converted with shocks of 40 watt-seconds or less, and two with 60, after 40 failed. Five patients were defibrillated by both the esophageal and the conventional, anteroposterior chest technics; the energy requirement with the esophageal method averaged less than one third of that with the conventional one. Four patients received 40, and one 30 watt-second shocks without anesthesia; all five tolerated the shocks well, and three of four who had had countershock previously under anesthesia, expressed preference for the esophageal technic without anesthesia in the future. All patients were observed carefully for any symptoms suggestive of esophageal injury or dysfunction. None such occurred, either immediately or within 4 months. We conclude that this technic may have a place in elective countershock in that it may allow cardioversion to be undertaken in many patients who would otherwise require anesthesia.
LMP1-augmented kappa intron enhancer activity contributes to upregulation expression of Ig kappa light chain via NF-kappaB and AP-1 pathways in nasopharyngeal carcinoma cells
Authors: HaiDan Liu, Hui Zheng, Zhi Duan, DuoSha Hu, Ming Li, SuFang Liu, ZiJian Li, XiYun Deng, ZhenLian Wang, Min Tang, Ying Shi, Wei Yi, Ya Cao
Journal: Molecular Cancer (2009)

Abstract Background Expression of kappa gene is under the control of distinct cis-regulatory elements, including the kappa intron enhancer (iE κ ) and the kappa 3' enhancer (3'E κ ). The active enhancers and expression of immunoglobulin is generally considered to be restricted to B lymphocytes. However, accumulating evidence indicated that epithelial cancer cells, including nasopharyngeal carcinoma (NPC) cell lines, express immunoglobulins. The mechanisms underlying the expression of Igs in nonlymphoid cells remain unknown. On the basis of our previous finding that expression of kappa light chain in NPC cells can be upregulated by EBV-encoded latent membrane protein 1(LMP1) through the activation of NF-κB and AP-1 signaling pathways, we thus use NPC cells as model to further explore the molecular mechanisms of nonlymphoid cells expressing Ig kappa. Results In this study, luciferase reporter plasmid containing human wild-type iE κ , and its derivative plasmids containing mutant binding sites for transcription factor NF-κB or AP-1 were constructed. Luciferase reporter assays demonstrate iE κ is active in Igκ-expressing NPC cells and LMP1 expression can upregulate the activity of iE κ in NPC cells. Mutation of the NF-κB or AP-1 site within and downstream the iE κ , inhibition of the NF-κB and AP-1 pathways by their respective chemical inhibitor Bay11-7082 and SP600125 as well as stable or transient expression of dominant-negative mutant of IκBα (DNMIκBα) or of c-Jun (TAM67) indicate that both sites are functional and LMP1-enhanced iE κ activity is partly regulated by these two sites. Gel shift assays show that LMP1 promotes NF-κB subunits p52 and p65 as well as AP-1 family members c-Jun and c-Fos binding to the κNF-κB and the κAP-1 motifs in vitro , respectively. Both chemical inhibitors and dominant negative mutants targeting for NF-κB and AP-1 pathways can attenuate the LMP1-enhanced bindings. Co-IP assays using nuclear extracts from HNE2-LMP1 cells reveal that p52 and p65, c-Jun and c-Fos proteins interact with each other at endogenous levels. ChIP assays further demonstrate p52 and p65 binding to the κB motif as well as c-Jun and c-Fos binding to the AP-1 motif of Ig kappa gene in vivo . Conclusion These results suggest that human iE κ is active in Igκ-expressing NPC cells and LMP1-stimulated NF-κB and AP-1 activation results in an augmenting activation of the iE κ . LMP1 promotes the interactions of heterodimeric NF-κB (p52/p65) and heterodimeric AP-1 (c-Jun/c-Fos) transcription factors with the human iE κ enhancer region are important for the upregulation of kappa light chain in LMP1-positive nasopharyngeal carcinoma cells.
Hyperhomocysteinemia Decreases Circulating High-Density Lipoprotein by Inhibiting Apolipoprotein A-I Protein Synthesis and Enhancing HDL Cholesterol Clearance
Authors: Dan Liao, Hongmei Tan, Rutai Hui, Zhaohui Li, Xiaohua Jiang, John Gaubatz, Fan Yang, William Durante, Lawrence Chan, Andrew I. Schafer, Henry J. Pownall, Xiaofeng Yang, Hong Wang
Journal: Circulation Research (2006)

We previously reported that hyperhomocysteinemia (HHcy), an independent risk factor of coronary artery disease (CAD), is associated with increased atherosclerosis and decreased plasma high-density lipoprotein cholesterol (HDL-C) in cystathionine beta-synthase-/apolipoprotein E-deficient (CBS(-/-)/apoE(-/-)) mice. We observed that plasma homocysteine (Hcy) concentrations are negatively correlated with HDL-C and apolipoprotein A1 (apoA-I) in patients with CAD. We found the loss of large HDL particles, increased HDL-free cholesterol, and decreased HDL protein in CBS(-/-)/apoE(-/-) mice, and attenuated cholesterol efflux from cholesterol-loaded macrophages to plasma in CBS(-/-)/apoE(-/-) mice. ApoA-I protein was reduced in the plasma and liver, but hepatic apoA-I mRNA was unchanged in CBS(-/-)/apoE(-/-) mice. Moreover, Hcy (0.5 to 2 mmol/L) reduced the levels of apoA-I protein but not mRNA and inhibited apoA-1 protein synthesis in mouse primary hepatocytes. Further, plasma lecithin:cholesterol acyltransferase (LCAT) substrate reactivity was decreased, LCAT specific activity increased, and plasma LCAT protein levels unchanged in apoE(-/-)/CBS(-/-) mice. Finally, the clearance of plasma HDL cholesteryl ester, but not HDL protein, was faster in CBS(-/-)/apoE(-/-) mice, correlated with increased scavenger receptor B1, and unchanged ATP-binding cassette transporter A1 protein expression in the liver. These findings indicate that HHcy inhibits reverse cholesterol transport by reducing circulating HDL via inhibiting apoA-I protein synthesis and enhancing HDL-C clearance.
Bone marrow stem cells and liver disease
Authors: Y N Kallis, M R Alison, S J Forbes
Journal: Gut (2006)

Stem cells are present in a variety of organs including the bone marrow (BM). Their role is to replenish multiple mature differentiated cell types and thereby achieve long-term tissue reconstitution. Stem cells retain the capacity to generate progeny and renew themselves throughout life. Haematopoietic stem cells (HSCs) are the main stem cell population within the BM and give rise to all mature blood lineages via erythroid, myelomonocytic and lymphoid precursors. A second type of bone marrow stem cell (BMSC), the mesenchymal stem cell (MSC), forms stromal tissue and can give rise to cells of mesodermal origin.

A longstanding principle of cell biology has been that cell loss is reconstituted via stem cells resident within and specific to an organ. However, recent work suggests that this paradigm may not hold for all organs or all types of injury, and tissue damage may attract migratory stem cell populations, particularly those from the BM. This observation has caused considerable interest in the field of liver disease, where new strategies to restore hepatocyte number, augment liver function and counteract progressive organ fibrosis are required. This article will focus on the various relationships between BMSCs and liver disease. It will concentrate on the evidence from animal models and human studies that BMSCs may aid in the regeneration of liver cell populations and may also contribute to the pathogenesis of liver damage. It will discuss the potential to use BMSCs for therapeutic application and review the current status of clinical trials in patients with liver disorders.

### The physiology of liver cell regeneration

The hepatic parenchyma is made up of hepatocytes and cholangiocytes. Unlike other organs such as the gut, liver cell mass is restored primarily through division of the majority of mature hepatocytes and not via a dedicated stem cell population. After a regenerative stimulus, such as a two-thirds partial hepatectomy, most …
RELATION BETWEEN PARAMETERS OF MYOCARDIAL MECHANICS AND VENTRICULO-ARTERIAL COUPLING: A THREE-DIMENSIONAL SPECKLE TRACKING STUDY IN HEALTHY ADULTS
Authors: Maryam Esmaeilzadeh, Hamid Salehi, Rabiya Malik, Hooman Bakhshandeh Abkenar, Ayan Patel, Natesa Pandian
Journal: Journal of the American College of Cardiology (2014)