tbuckley/cabot-search huggingface dataset:
Epstein–Barr Virus Infection as an Epigenetic Driver of Tumorigenesis
Authors: Atsushi Kaneda, Keisuke Matsusaka, Hiroyuki Aburatani, Masashi Fukayama
Journal: Cancer Research (2012)

Abstract Epstein–Barr virus (EBV) establishes latent infection and is associated with tumors, such as Burkitt lymphoma, nasopharyngeal carcinoma, and gastric cancers. We recently reported that EBV+ gastric cancer shows an EBV+/extensively high-methylation epigenotype, and in vitro EBV infection induces extensive DNA methylation with gene repression within 18 weeks. On the basis of the absence of both EBV and high-methylation accumulation in the surrounding mucosa of EBV+ gastric cancer, it is suggested that an EBV-infected cell acquires extensive methylation to silence multiple tumor suppressor genes in a short time period and transforms into cancer cells, not forming a precancerous field with EBV infection or methylation accumulation. The methylation mechanism induced by EBV infection has not been fully clarified. Differences in EBV genome methylation that are dependent on a different latency status or other epigenomic alterations, such as 3-dimensional conformation and histone modification, may affect host genome methylation. Expressions of viral proteins and small RNAs are also different depending on latency status, and some viral proteins might trigger DNA methylation by inducing DNA methyltransferase overexpression. In this review, we discuss these roles of EBV infection in driving tumorigenesis and their possible association with aberrant DNA methylation. Cancer Res; 72(14); 3445–50. ©2012 AACR.
Topical propylene glycol and hyperosmolality
Authors: C.A. COMMENS
Journal: British Journal of Dermatology (1990)

Topical propylene glycol is known to cause elevated serum osmolality in burns patients. Twelve adults with skin disease had quantities of propylene glycol applied to their skin to a maximum of 6.1 g/kg per 24 h for 5 days. Serum electrolyte, lactate and osmolality results remained unchanged during the study. These results suggest that topical propylene glycol may be used in adult dermatological practice without affecting serum osmolality.
Ablation of electrograms with an isolated, delayed component as treatment of unmappable monomorphic ventricular tachycardias in patients with structural heart disease
Authors: Angel Arenal, Esteban Glez-Torrecilla, Mercedes Ortiz, Julian Villacastín, Javier Fdez-Portales, Elena Sousa, Silvia del Castillo, Leopoldo Perez de Isla, Javier Jimenez, Jesus Almendral
Journal: Journal of the American College of Cardiology (2002)
Estradiol counteracts oxidized LDL-induced asymmetric dimethylarginine production by cultured human endothelial cells
Authors: E MONSALVE, P OVIEDO, M GARCIAPEREZ, J TARIN, A CANO, C HERMENEGILDO
Journal: Cardiovascular Research (2006)

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase, is a novel cardiovascular risk factor produced by endothelial cells. ADMA levels are mainly regulated by the activity of dimethylarginine dimethylaminohydrolases (DDAH). Endothelial release of ADMA is increased in the presence of oxidized LDL cholesterol (oxLDL), whereas estrogens stimulate NO production by endothelial cells by increasing both expression and activity of NO synthase and by reducing ADMA levels. Thus, the aim of the present study was to evaluate the estradiol effects on the DDAH/ADMA/NO pathway in cultured human umbilical vein endothelial cells (HUVEC) exposed to LDL.After 24 h of exposure to various treatments, culture medium was collected to measure NO production by using an amperometric sensor specific for NO, and to measure dimethylarginines by high-performance liquid chromatography (HPLC). DDAH-I and II mRNA expression and protein content were quantified by real-time PCR assay and immunoblotting, respectively.Exposure of HUVEC to 100 microg/mL oxLDL, but not to 100 microg/mL of native LDL (nLDL), reduced DDAH-II expression at both the mRNA as well as the protein levels, which in turn increased ADMA levels and reduced NO production. Estradiol (1 nM) alone increased DDAH-II mRNA and protein expression, which reduced ADMA levels and increased NO production. In cells exposed to estradiol in combination with either nLDL or oxLDL, levels of DDAH-II, ADMA, and NO were the same as those for estradiol alone.Estradiol completely reverses the effects induced by oxLDL on the DDAH/ADMA/NO pathway.
Complete response in a patient with colonic mantle cell lymphoma with multiple lymphomatous polyposis treated with combination chemotherapy using anti-CD20 antibody and cladribine
Authors: T. Watanabe, N. Homma, N. Ogata, H. Saito, T. Kanefuji, K. Hasegawa, K. Soga, K. Shibasaki, T. Endo, Y. Ajioka
Journal: Gut (2007)

A 59-year-old woman suspected of having colonic malignant lymphoma was transferred to our hospital (Japan Labour Health and Welfare Organization Tsubame Rosai Hospital, Tsubame, Niigata, Japan) in October 2003. Systemic CT scan showed no swollen lymph nodes. Gallium scintiscan useful in localising lymphoma, showed no abnormal accumulation. Endoscopic findings of the oesophagogastroduodenal tract showed no tumour lesions. Colonoscopic examination was performed in November 2003, and clearly revealed multiple small elevations (fig 1A). Endoscopic mucosal resections were performed on lesions and the resected specimens suggested mantle cell lymphoma (MCL). A second colonoscopic examination performed in July 2004 revealed increased numbers of polyps, indicating a case of multiple lymphomatous polyposis (MLP). Biopsy was performed again to confirm the diagnosis of colonic MCL. Figure 1B–D shows the histopathological findings of both resected and biopsy specimens. Immunohistochemical examination of these specimens revealed positive immunoreactivity for CD20 and CD5 (fig 1E), and negative …
The path towards universal health coverage in the Arab uprising countries Tunisia, Egypt, Libya, and Yemen
Authors: Shadi S Saleh, Mohamad S Alameddine, Nabil M Natafgi, Awad Mataria, Belgacem Sabri, Jamal Nasher, Moez Zeiton, Shaimaa Ahmad, Sameen Siddiqi
Journal: The Lancet (2014)
Balance of Treg vs. T-helper cells in the transition from symptomless to lesional psoriatic skin
Authors: R.R.M.C. Keijsers, H.M.J. van der Velden, P.E.J. van Erp, R.T. de Boer-van Huizen, I. Joosten, H.J.P.M. Koenen, P.C.M. van de Kerkhof
Journal: British Journal of Dermatology (2013)

In the pathogenesis of psoriasis, proinflammatory T cells are strongly involved in the inflammatory process, where regulatory T-cell (Treg) function is impaired.As effective Treg function is associated with a numerical balance between Treg and effector T cells, we wondered whether Treg/T-helper cell ratios may be associated with certain stages of the inflammatory process. We opted for the margin zone model as a dynamic approach.From nine patients with chronic plaque psoriasis, 3-mm punch biopsies were obtained from the centre and margin of the lesion, perilesional skin and distant uninvolved skin. Skin biopsies of 10 healthy volunteers were included as a control. Samples were analysed using immunohistochemistry and immunofluorescence.In the transition from symptomless to lesional skin, a significant increase of CD3+, CD4+ and Foxp3+ cells was found. In seven of nine patients the ratio of Treg (Foxp3+) vs. CD4+ T cells was higher in the distant uninvolved skin than in the perilesional and lesional skin. Interestingly, the Foxp3/CD4 ratio in the distant uninvolved skin was even higher than in the skin of healthy controls. Notably, we found that most of the interleukin (IL)-17 expression was not related to CD4+ cells, but to mast cells.The relatively high Foxp3/CD4 ratio in symptomless skin of patients with psoriasis suggests an active immune controlling mechanism distant from the psoriatic plaque. In the margin and centre of the plaque the ratio appears skewed towards effector cells associated with inflammation. IL-17, an important driver of the psoriatic process, is mostly related to mast cells, and only sporadically to T cells.
Therapeutic Applications of Extracellular Vesicles: Clinical Promise and Open Questions
Authors: Bence György, Michelle E. Hung, Xandra O. Breakefield, Joshua N. Leonard
Journal: The Annual Review of Pharmacology and Toxicology (2014)

This review provides an updated perspective on rapidly proliferating efforts to harness extracellular vesicles (EVs) for therapeutic applications. We summarize current knowledge, emerging strategies, and open questions pertaining to clinical potential and translation. Potentially useful EVs comprise diverse products of various cell types and species. EV components may also be combined with liposomes and nanoparticles to facilitate manufacturing as well as product safety and evaluation. Potential therapeutic cargoes include RNA, proteins, and drugs. Strategic issues considered herein include choice of therapeutic agent, means of loading cargoes into EVs, promotion of EV stability, tissue targeting, and functional delivery of cargo to recipient cells. Some applications may harness natural EV properties, such as immune modulation, regeneration promotion, and pathogen suppression. These properties can be enhanced or customized to enable a wide range of therapeutic applications, including vaccination, improvement of pregnancy outcome, and treatment of autoimmune disease, cancer, and tissue injury.
Inbreeding and Canine Mammary Cancer: A Retrospective Study2
Authors: C. Richard Dorn, Robert Schneider
Journal: JNCI Journal of the National Cancer Institute (1976)

Using files of the Animal Neoplasm Registry (ANR) in Alameda and Contra Costa Counties, California, we conducted a retrospective study to compare the degree of inbreeding in the ancestry of purebred dogs with mammary and other cancers, and of those without tumors. Wright's coefficients of inbreeding, calculated for all animals in the three groups, ranged from 0.000 to 0.535. The median inbreeding coefficients of the mammary cancer and comparison groups (consisting of other cancers) were approximately twice that of the nonneoplastic group, but neither difference was statistically significant. Dogs with mammary adenocarcinoma and mixed mammary cancer had similar degrees of inbreeding.
Phospholipase A2 inhibitors protect against prion and Aβ mediated synapse degeneration
Authors: Clive Bate, Mourad Tayebi, Alun Williams
Journal: Molecular Neurodegeneration (2010)

An early event in the neuropathology of prion and Alzheimer's diseases is the loss of synapses and a corresponding reduction in the level of synaptophysin, a pre-synaptic membrane protein essential for neurotransmission. The molecular mechanisms involved in synapse degeneration in these diseases are poorly understood. In this study the process of synapse degeneration was investigated by measuring the synaptophysin content of cultured neurones incubated with the prion derived peptide (PrP82-146) or with Aβ1-42, a peptide thought to trigger pathogenesis in Alzheimer's disease. A pharmacological approach was used to screen cell signalling pathways involved in synapse degeneration. Pre-treatment with phospholipase A2 inhibitors (AACOCF3, MAFP and aristolochic acids) protected against synapse degeneration in cultured cortical and hippocampal neurones incubated with PrP82-146 or Aβ1-42. Synapse degeneration was also observed following the addition of a specific phospholipase A2 activating peptide (PLAP) and the addition of PrP82-146 or Aβ1-42 activated cytoplasmic phospholipase A2 within synapses. Activation of phospholipase A2 is the first step in the generation of platelet-activating factor (PAF) and PAF receptor antagonists (ginkgolide B, Hexa-PAF and CV6029) protected against synapse degeneration induced by PrP82-146, Aβ1-42 and PLAP. PAF facilitated the production of prostaglandin E2, which also caused synapse degeneration and pre-treatment with the prostanoid E receptor antagonist AH13205 protected against PrP82-146, Aβ1-42 and PAF induced synapse degeneration. Our results are consistent with the hypothesis that PrP82-146 and Aβ1-42trigger abnormal activation of cytoplasmic phospholipase A2 resident within synapses, resulting in elevated levels of PAF and prostaglandin E2that cause synapse degeneration. Inhibitors of this pathway that can cross the blood brain barrier may protect against the synapse degeneration seen during Alzheimer's or prion diseases.
Effects of Bariatric Surgery on Mortality in Swedish Obese Subjects
Authors: Lars Sjöström, Kristina Narbro, C. David Sjöström, Kristjan Karason, Bo Larsson, Hans Wedel, Ted Lystig, Marianne Sullivan, Claude Bouchard, Björn Carlsson, Calle Bengtsson, Sven Dahlgren, Anders Gummesson, Peter Jacobson, Jan Karlsson, Anna-Karin Lindroos, Hans Lönroth, Ingmar Näslund, Torsten Olbers, Kaj Stenlöf, Jarl Torgerson, Göran Ågren, Lena M.S. Carlsson
Journal: New England Journal of Medicine (2007)

Obesity is associated with increased mortality. Weight loss improves cardiovascular risk factors, but no prospective interventional studies have reported whether weight loss decreases overall mortality. In fact, many observational studies suggest that weight reduction is associated with increased mortality.The prospective, controlled Swedish Obese Subjects study involved 4047 obese subjects. Of these subjects, 2010 underwent bariatric surgery (surgery group) and 2037 received conventional treatment (matched control group). We report on overall mortality during an average of 10.9 years of follow-up. At the time of the analysis (November 1, 2005), vital status was known for all but three subjects (follow-up rate, 99.9%).The average weight change in control subjects was less than +/-2% during the period of up to 15 years during which weights were recorded. Maximum weight losses in the surgical subgroups were observed after 1 to 2 years: gastric bypass, 32%; vertical-banded gastroplasty, 25%; and banding, 20%. After 10 years, the weight losses from baseline were stabilized at 25%, 16%, and 14%, respectively. There were 129 deaths in the control group and 101 deaths in the surgery group. The unadjusted overall hazard ratio was 0.76 in the surgery group (P=0.04), as compared with the control group, and the hazard ratio adjusted for sex, age, and risk factors was 0.71 (P=0.01). The most common causes of death were myocardial infarction (control group, 25 subjects; surgery group, 13 subjects) and cancer (control group, 47; surgery group, 29).Bariatric surgery for severe obesity is associated with long-term weight loss and decreased overall mortality.
Chmp 1A is a mediator of the anti-proliferative effects of All-trans Retinoic Acid in human pancreatic cancer cells
Authors: Jing Li, Brandon Orr, Kayla White, Natalia Belogortseva, Richard Niles, Goran Boskovic, Hanh Nguyen, Ava Dykes, Maiyon Park
Journal: Molecular Cancer (2009)

Abstract Background We recently have shown that Charged multivesicular protein/Chromatin modifying protein1A (Chmp1A) functions as a tumor suppressor in human pancreatic tumor cells. Pancreatic cancer has the worst prognosis of all cancers with a dismal 5-year survival rate. Preclinical studies using ATRA for treating human pancreatic cancer suggest this compound might be useful for treatment of pancreatic cancer patients. However, the molecular mechanism by which ATRA inhibits growth of pancreatic cancer cells is not clear. The objective of our study was to investigate whether Chmp1A is involved in ATRA-mediated growth inhibition of human pancreatic tumor cells. Results We performed microarray studies using HEK 293T cells and discovered that Chmp1A positively regulated Cellular retinol-binding protein 1 (CRBP-1). CRBP-1 is a key regulator of All-trans retinoic acid (ATRA) through ATRA metabolism and nuclear localization. Since our microarray data indicates a potential involvement of Chmp1A in ATRA signaling, we tested this hypothesis by treating pancreatic tumor cells with ATRA in vitro . In the ATRA-responsive cell lines, ATRA significantly increased the protein expression of Chmp1A, CRBP-1, P53 and phospho-P53 at serine 15 and 37 position. We found that knockdown of Chmp1A via shRNA abolished the ATRA-mediated growth inhibition of PanC-1 cells. Also, Chmp1A silencing diminished the increase of Chmp1A, P53 and phospho-P53 protein expression induced by ATRA. In the ATRA non-responsive cells, ATRA did not have any effect on the protein level of Chmp1A and P53. Chmp1A over-expression, however, induced growth inhibition of ATRA non-responsive cells, which was accompanied by an increase of Chmp1A, P53 and phospho-P53. Interestingly, in ATRA responsive cells Chmp1A is localized to the nucleus, which became robust upon ATRA treatment. In the ATRA-non-responsive cells, Chmp1A was mainly translocated to the plasma membrane upon ATRA treatment. Conclusion Collectively our data provides evidence that Chmp1A mediates the growth inhibitory activity of ATRA in human pancreatic cancer cells via regulation of CRBP-1. Our results also suggest that nuclear localization of Chmp1A is important in mediating ATRA signaling.
Upregulation of Nox4 by TGFβ1 Oxidizes SERCA and Inhibits NO in Arterial Smooth Muscle of the Prediabetic Zucker Rat
Authors: XiaoYong Tong, Xiuyun Hou, David Jourd'heuil, Robert M. Weisbrod, Richard A. Cohen
Journal: Circulation Research (2010)

Rationale: Vascular smooth muscle cell (SMC) migration is an important pathological process in several vascular occlusive diseases, including atherosclerosis and restenosis, both of which are accelerated by diabetes mellitus. Objective: To determine the mechanisms of abnormal vascular SMC migration in type 2 diabetes, the obese Zucker rat (ZO), a model of obesity and insulin resistance, was studied. Methods and Results: In culture, ZO aortic SMCs showed a significant increase in Nox4 mRNA and protein levels compared with the control lean Zucker rat (ZL). The sarco-/endoplasmic reticulum Ca 2+ ATPase (SERCA) nitrotyrosine-294,295 and cysteine-674 (C674)-SO 3 H were increased in ZO SMCs, indicating oxidant stress. Unlike ZL SMC, nitric oxide (NO) failed to inhibit serum-induced SMC migration in ZO. Transfection of Nox4 small interference RNA or overexpression of SERCA2b wild type, but not C674S mutant SERCA, restored the response to NO. Knockdown of Nox4 also decreased SERCA oxidation in ZO SMCs. In addition, transforming growth factor-β1 via Smad2 was necessary and sufficient to upregulate Nox4, oxidize SERCA, and block the antimigratory action of NO in ZO SMCs. Corresponding to the results in cultured SMCs, immunohistochemistry confirmed that Nox4 and SERCA C674-SO 3 H were significantly increased in ZO aorta. After common carotid artery injury, knockdown of Nox4 by adenoviral Nox4 short hairpin RNA decreased Nox4 and SERCA C674-SO 3 H staining and significantly decreased injury-induced neointima. Conclusion: These studies indicate that the upregulation of Nox4 by transforming growth factor-β1 in ZO SMCs is responsible for the impaired response to NO by a mechanism involving the oxidation of SERCA C674. Knockdown of Nox4 inhibits oxidation of SERCA, as well as neointima formation, after ZO common carotid artery injury.
Roadway Proximity and Risk of Sudden Cardiac Death in Women
Authors: Jaime E. Hart, Stephanie E. Chiuve, Francine Laden, Christine M. Albert
Journal: Circulation (2014)

Sudden cardiac death (SCD) is a major source of mortality and is the first manifestation of heart disease for the majority of cases. Thus, there is a definite need to identify risk factors for SCD that can be modified at the population level. Exposure to traffic, measured by residential roadway proximity, has been shown to be associated with an increased risk of cardiovascular disease. Our objective was to determine whether roadway proximity was associated with an increased risk of SCD and to compare that risk with the risk of other coronary heart disease outcomes.A total of 523 cases of SCD were identified over 26 years of follow-up among 107 130 members of the prospective Nurses' Health Study. We calculated residential distance to roadways at all residential addresses from 1986 to 2012. In age- and race-adjusted models, women living within 50 m of a major roadway had an elevated risk of SCD (hazard ratio=1.56; 95% confidence interval, 1.18-2.05). The association was attenuated but still statistically significant after controlling for potential confounders and mediators (hazard ratio=1.38; 95% confidence interval, 1.04-1.82). The equivalent adjusted hazard ratios for nonfatal myocardial infarction and fatal coronary heart disease were 1.08 (95% confidence interval, 0.96-1.23) and 1.24 (95% confidence interval, 1.03-1.50), respectively.Among this sample of middle-aged and older women, roadway proximity was associated with elevated and statistically significant risks of SCD and fatal coronary heart disease, even after controlling for other cardiovascular risk factors.
Medical and Surgical Treatment of the Wolff-Parkinson-White Syndrome
Authors: D Durrer
Journal: Annual Review of Medicine (1976)

Few chapters of electrocardiography have made such rapid progress in the last decade as the Wolff-Parkinson-White (WPW) syndrome. The introduction of new techniques (I, 2), or of older ones, such as electric stimulation of the heart, made safe for clinical-physiological investigations (3, 4), is responsible for this break­ through and illustrates Carl Ludwig's dictum: Die Methode ist alles. A relatively simple hypothesis appears to be adequate for an understanding of many morphologi­ cal ECG aspects of this syndrome, the genesis of arrhythmias, and the influence of drugs on their causative mechanisms. What follows is a bird's-eye view (5-8).
Screening for Acute <i>I</i> <sub>Kr</sub> Block Is Insufficient to Detect Torsades de Pointes Liability
Authors: Tao Yang, Young Wook Chun, Dina M. Stroud, Jonathan D. Mosley, Bjorn C. Knollmann, Charles Hong, Dan M. Roden
Journal: Circulation (2014)

Background— New drugs are routinely screened for I Kr blocking properties thought to predict QT prolonging and arrhythmogenic liability. However, recent data suggest that chronic (hours) drug exposure to phosphoinositide 3-kinase inhibitors used in cancer can prolong QT by inhibiting potassium currents and increasing late sodium current ( I Na-L ) in cardiomyocytes. We tested the extent to which I Kr blockers with known QT liability generate arrhythmias through this pathway. Methods and Results— Acute exposure to dofetilide, an I Kr blocker without other recognized electropharmacologic actions, produced no change in ion currents or action potentials in adult mouse cardiomyocytes, which lack I Kr . By contrast, 2 to 48 hours of exposure to the drug generated arrhythmogenic afterdepolarizations and ≥15-fold increases in I Na-L . Including phosphatidylinositol 3,4,5-trisphosphate, a downstream effector for the phosphoinositide 3-kinase pathway, in the pipette inhibited these effects. I Na-L was also increased, and inhibitable by phosphatidylinositol 3,4,5-trisphosphate, with hours of dofetilide exposure in human-induced pluripotent stem cell–derived cardiomyocytes and in Chinese hamster ovary cells transfected with SCN5A , encoding sodium current. Cardiomyocytes from dofetilide-treated mice similarly demonstrated increased I Na-L and afterdepolarizations. Other agents with variable I Kr -blocking potencies and arrhythmia liability produced a range of effects on I Na-L , from marked increases (E-4031, d -sotalol, thioridazine, and erythromycin) to little or no effect (haloperidol, moxifloxacin, and verapamil). Conclusions— Some but not all drugs designated as arrhythmogenic I Kr blockers can generate arrhythmias by augmenting I Na-L through the phosphoinositide 3-kinase pathway. These data identify a potential mechanism for individual susceptibility to proarrhythmia and highlight the need for a new paradigm to screen drugs for QT prolonging and arrhythmogenic liability.