tbuckley/cabot-search huggingface dataset:
Lymphocyte Transformation by Pim-2 Is Dependent on Nuclear Factor-κB Activation
Authors: Peter S. Hammerman, Casey J. Fox, Ryan M. Cinalli, Anne Xu, John D. Wagner, Tullia Lindsten, Craig B. Thompson
Journal: Cancer Research (2004)

Pim-2 is a transcriptionally regulated oncogenic kinase that promotes cell survival in response to a wide variety of proliferative signals. Deregulation of Pim-2 expression has been documented in several human malignancies, including leukemia, lymphoma, and multiple myeloma. Here, we show that the ability of Pim-2 to promote survival of cells is dependent on nuclear factor (NF)-kappaB activation. Pim-2 activates NF-kappaB-dependent gene expression by inducing phosphorylation of the oncogenic serine/threonine kinase Cot, leading to both augmentation of IkappaB kinase activity and a shift in nuclear NF-kappaB from predominantly p50 homodimers to p50/p65 heterodimers. Blockade of NF-kappaB function eliminates Pim-2-mediated survival in both cell lines and primary cells, and both Cot phosphorylation and expression are required for the prosurvival effects of Pim-2. Although Pim-2 cooperates with Myc to promote growth factor-independent cell proliferation, this feature is abrogated by NF-kappaB blockade. The ability of Pim-2 to serve as an oncogene in vivo depends on sustained NF-kappaB activity. Thus, the transcriptional induction of Pim-2 initiates a novel NF-kappaB activation pathway that regulates cell survival.
Evaluation of cell types for assessment of cytogenetic damage in arsenic exposed population
Authors: Pritha Ghosh, Arindam Basu, Keshav K Singh, Ashok K Giri
Journal: Molecular Cancer (2008)

Abstract Background Cytogenetic biomarkers are essential for assessing environmental exposure, and reflect adverse human health effects such as cellular damage. Arsenic is a potential clastogen and aneugen. In general, the majority of the studies on clastogenic effects of arsenic are based on frequency of micronuclei (MN) study in peripheral lymphocytes, urothelial and oral epithelial cells. To find out the most suitable cell type, here, we compared cytogenetic damage through MN assay in (a) various populations exposed to arsenic through drinking water retrieved from literature review, as also (b) arsenic-induced Bowen's patients from our own survey. Results For literature review, we have searched the Pubmed database for English language journal articles using the following keywords: "arsenic", "micronuclei", "drinking water", and "human" in various combinations. We have selected 13 studies consistent with our inclusion criteria that measured micronuclei in either one or more of the above-mentioned three cell types, in human samples. Compared to urothelial and buccal mucosa cells, the median effect sizes measured by the difference between people with exposed and unexposed, lymphocyte based MN counts were found to be stronger. This general pattern pooled from 10 studies was consistent with our own set of three earlier studies. MN counts were also found to be stronger for lymphocytes even in arsenic-induced Bowen's patients (cases) compared to control individuals having arsenic-induced non-cancerous skin lesions. Conclusion Overall, it can be concluded that MN in lymphocytes may be superior to other epithelial cells for studying arsenic-induced cytogenetic damage.
Metastasis Suppression by Breast Cancer Metastasis Suppressor 1 Involves Reduction of Phosphoinositide Signaling in MDA-MB-435 Breast Carcinoma Cells
Authors: Daryll B. DeWald, Javad Torabinejad, Rajeev S. Samant, Derrick Johnston, Nuray Erin, Joseph C. Shope, Yi Xie, Danny R. Welch
Journal: Cancer Research (2005)

Abstract Several molecules that suppress metastasis without suppressing tumorigenicity have been identified, but their mechanisms of action have not yet been determined. Many block growth at the secondary site, suggesting involvement in how cells respond to signals from the extracellular milieu. Breast cancer metastasis suppressor 1 (BRMS1)–transfected MDA-MB-435 cells were examined for modifications of phosphoinositide signaling as a potential mechanism for metastasis suppression. 435/BRMS1 cells expressed &amp;lt;10% of phosphatidylinositol-4, 5-bisphosphate compared with parental cells, whereas levels of the PtdIns(4)P and phosphatidylinositol-3-phosphate were unchanged. Inositol (1,4,5)-trisphosphate [Ins(1,4,5)P3] were decreased in 435/BRMS1 cells by ∼50%. Phosphatidylinositol-3,4,5-trisphosphate levels were undetectable in 435/BRMS1 cells, even when stimulated by exogenous insulin or platelet-derived growth factor. Immunofluorescence microscopy to examine cellular distribution confirmed that phosphatidylinositol-4,5-bisphosphate distribution with cells was unchanged but was uniformly decreased throughout the cell. Although the gross morphology of 435/BRMS1 cells is similar to the parent, filamentous actin was more readily apparent in 435/BRMS1. Intracellular calcium, measured using Fluo-3 and Fura-2 fluorescent calcium indicator dyes, was somewhat lower, but not statistically different in 435/BRMS1 compared with parental cell. However, when stimulated with platelet-derived growth factor, MDA-MB-435 cells, but not 435/BRMS1 cells mobilized intracellular calcium. Taken together, these results implicate signaling through phosphoinositides in the regulation of breast cancer metastasis, specifically metastasis that can be suppressed by BRMS1.
Combinations of Maternal KIR and Fetal HLA-C Genes Influence the Risk of Preeclampsia and Reproductive Success
Authors: Susan E. Hiby, James J. Walker, Kevin M. O'Shaughnessy, Christopher W.G. Redman, Mary Carrington, John Trowsdale, Ashley Moffett
Journal: The Journal of Experimental Medicine (2004)

Preeclampsia is a serious complication of pregnancy in which the fetus receives an inadequate supply of blood due to failure of trophoblast invasion. There is evidence that the condition has an immunological basis. The only known polymorphic histocompatibility antigens on the fetal trophoblast are HLA-C molecules. We tested the idea that recognition of these molecules by killer immunoglobulin receptors (KIRs) on maternal decidual NK cells is a key factor in the development of preeclampsia. Striking differences were observed when these polymorphic ligand: receptor pairs were considered in combination. Mothers lacking most or all activating KIR (AA genotype) when the fetus possessed HLA-C belonging to the HLA-C2 group were at a greatly increased risk of preeclampsia. This was true even if the mother herself also had HLA-C2, indicating that neither nonself nor missing-self discrimination was operative. Thus, this interaction between maternal KIR and trophoblast appears not to have an immune function, but instead plays a physiological role related to placental development. Different human populations have a reciprocal relationship between AA frequency and HLA-C2 frequency, suggesting selection against this combination. In light of our findings, reproductive success may have been a factor in the evolution and maintenance of human HLA-C and KIR polymorphisms.
Autocrine-paracrine VEGF loops potentiate the maturation of megakaryocytic precursors through Flt1 receptor
Authors: Ida Casella, Tiziana Feccia, Cristiana Chelucci, Paola Samoggia, Germana Castelli, Raffaella Guerriero, Isabella Parolini, Eleonora Petrucci, Elvira Pelosi, Ornella Morsilli, Marco Gabbianelli, Ugo Testa, Cesare Peschle
Journal: Blood (2003)
In Vivo Effect of Some Naphthalene-Related Compounds on Aryl Hydrocarbon (Benzo[a]pyrene) Hydroxylase
Authors: K. Alexandrov, C. Frayssinet
Journal: JNCI Journal of the National Cancer Institute (1973)

Naphthalene injected intraperitoneally inhibited aryl hydrocarbon (benzo[a]pyrene) hydroxylase (AHH) in rat liver homogenatc and microsomal preparations. Pretreatment with naphthalene also decreased the induction of this enzyme by methylcholanthrene, a strong inducer of AHH. However, 1,3-naphthalenediol slightly increased the level of AHH in liver, whereas 2-methyl-β-naphthothiazole increased AHH in both liver and lung. 1-Naphthylamine, 2-naphthylamine, and 1,8-diaminonaphtha-lene increased AHH in lung and especially in kidney homogenates and microsome preparations. 1-Naphthol, 2-naphthol, 1-naphthonitrile, 2-naphthonitrile, 1-naphthyl phosphordicloridatc, and 2-naphthyl phosphordicloridate had no effect on AHH.
CELLULAR AND MOLECULAR BIOLOGY OF ALZHEIMER'S DISEASE AND ANIMAL MODELS
Authors: Donald L. Price, M.D, Sangram S. Sisodia, Ph.D
Journal: Annual Review of Medicine (1994)

Alzheimer's disease (AD), the most common dementing disorder of late life, is a major cause of disability and death in the elderly. Neurobiological, genetic, and molecular studies have defined the vulnerable neural systems, abnormalities in cytoskeletal proteins in neurons, the biology of the beta-amyloid precursor protein (APP) and beta-amyloid (A beta, beta A4), and several APP mutations linked to the disease. More recently, investigators have begun to develop animal models essential for delineating pathogenetic mechanisms and for developing and testing new therapies for treating AD in humans. This review focuses primarily on recent progress in investigation of animal models of AD (including aged nonhuman primates and transgenic mice), which have begun to clarify some of the questions raised by investigation of the disease in humans.
An Increase in Bronchial Responsiveness Is Associated with Continuing or Restarting Smoking
Authors: Susan Chinn, Deborah Jarvis, Christina M. Luczynska, Ursula Ackermann-Liebrich, Josep M. Antó, Isa Cerveri, Roberto de Marco, Thorarinn Gislason, Joachim Heinrich, Christer Janson, Nino Künzli, Bénédicte Leynaert, Françoise Neukirch, Jan P. Schouten, Jordi Sunyer, Cecilie Svanes, Matthias Wjst, Peter G. Burney
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Rationale: Bronchial responsiveness (BHR) has been found to be associated with smoking, atopy, and lower lung function in cross-sectional studies, but there is little information on determinants of change in adults.Objectives: To analyze change in bronchial responsiveness in an international longitudinal community study.Methods: The study was performed in 3,993 participants in the European Community Respiratory Health Survey who had bronchial responsiveness measured in 1991–1993, when aged 20 to 44 yr, and in 1998–2002.Measurements: Bronchial responsiveness was assessed by methacholine challenge. Serum samples were tested for total IgE, and for specific IgE to four common allergens. Smoking information was obtained from detailed administered questionnaires. Change in bronchial responsiveness was analyzed by change in IgE sensitization, smoking, and lung function, with tests of interaction terms with age and sex.Main Results: Continuing and restarting smokers had increasing bronchial responsiveness, approximately equivalent to a mean reduction in PD20 of 0.68 and 0.75 doubling doses, respectively, over 10 yr, in addition to a small increase explained by decline in FEV1. No other risk factor for change in bronchial responsiveness was identified.Conclusions: Smoking is a risk factor for increasing bronchial responsiveness over and above the effect of decreasing lung function. Neither baseline IgE sensitization nor change in sensitization was shown to be a risk factor for increasing BHR, the latter possibly due to little overall increase or decrease in sensitization.
Cellular vacuolization and apoptosis induced by hepatitis B virus large surface protein
Authors: N Foo
Journal: Hepatology (2002)

Fibrosing cholestatic hepatitis (FCH) is a rapidly progressive form of viral hepatitis B that occurs in severely immunosuppressed patients. Pathologically, the liver in FCH is characterized by widespread hepatocyte vacuolization and apoptosis, which, in contrast to more common forms of hepatitis B, is only rarely associated with significant inflammation. Therefore, it has been proposed that, in FCH, hepatocytes may be injured by a direct cytopathic effect of the virus rather than by the host immune response. In support of this hypothesis, we present evidence that cultured hepatoma cells that had been transfected with a plasmid selectively expressing the viral large surface protein form numerous large vacuoles and undergo apoptosis. The similarity of the cytopathology in FCH in vivo and in these transfected cells in vitro strongly implicates the large surface protein as the direct cause of this acute liver disease. This conclusion is further supported by the published demonstration that hepatocytes tend to accumulate large surface protein in FCH, which may reflect its overexpression by the virus. In conclusion, our data implicate the large surface protein as a major cause of hepatocyte injury in fibrosing cholestatic hepatitis. (HEPATOLOGY2002;36:1400–1407).
Vitamin D Deficiency in Homebound Elderly Persons
Authors: F. Michael Gloth
Journal: JAMA (1995)

<h3>Objective.</h3> —To assess the vitamin D status in homebound, community-dwelling elderly persons; sunlight-deprived elderly nursing home residents; and healthy, ambulatory elderly persons. <h3>Design.</h3> —A cohort analytic study. <h3>Participants.</h3> —Of 244 subjects at least 65 years old, 116 subjects (85 women and 31 men) had been confined indoors for at least 6 months, either in private dwellings in the community (the Hopkins Elder Housecall Program) or in a teaching nursing home (The Johns Hopkins Geriatrics Center). The 128 control subjects, a healthy ambulatory group, came from the Baltimore Longitudinal Study on Aging. All subjects were free of diseases or medications that might interfere with their vitamin D status. <h3>Main Outcome Measures.</h3> —Serum levels of 25-hydroxyvitamin D (25-OHD) and 1,25-dihydroxyvitamin D (1,25-[OH]<sub>2</sub>D) were measured in all subjects. In a subgroup of 80 subjects, serum levels of intact parathyroid hormone (PTH), ionized calcium, and osteocalcin and intake of vitamin D (through 3-day food records) were assessed. A randomly selected cohort of sunlight-deprived subjects also had serum levels of vitamin D binding protein measured. <h3>Results.</h3> —In sunlight-deprived subjects overall, the mean 25-OHD level was 30 nmol/L (12 ng/mL) (range, &lt; 10 to 77 nmol/L [&lt;4 to 31 ng/mL]) and the mean 1,25-(OH)<sub>2</sub>D level was 52 pmol/L (20 pg/mL) (range, 18 to 122 pmol/L [7 to 47 pg/mL]). In the sunlight-deprived subjects, 54% of community dwellers and 38% of nursing home residents had serum levels of 25-OHD below 25 nmol/L (10 ng/mL) (normal range, 25 to 137 nmol/L [10 to 55 ng/mL]). A significant inverse relationship existed between 25-OHD (ie, Log [25-OHD]) and PTH when they were analyzed together (<i>r</i>=-0.42;<i>R</i><sup>2</sup>=0.18;<i>P</i>&lt;.001) and for each cohort separately. All other parameters measured, except ionized calcium, differed significantly from the Baltimore Longitudinal Study Group means. The mean (SD) daily intakes of vitamin D (121 [132] IU) and calcium (583 [322] mg) were below the recommended dietary allowance only in the community-dwelling homebound population. The mean vitamin D binding protein level in the sunlight-deprived subgroup was in the normal range. <h3>Conclusions.</h3> —Despite a relatively high degree of vitamin supplementation in the United States, homebound elderly persons are likely to suffer from vitamin D deficiency. (<i>JAMA</i>. 1995;274:1683-1686)
PTU-029 University Hospitals of Leicester Colonoscopy Audit 2011–2012
Authors: A Sasegbon, N Hossain
Journal: Gut (2013)

<h3>Introduction</h3> <h3>Aims</h3> and Objectives: To: Assess the success rate of all colonoscopies carried out in University Hospitals of Leicester (UHL) NHS Trust between September 2011 and 2012. This will then be compared with the results of audits in 2006–2007, 2007–2008, and 2010–2011. Assess the complication rate and reasons for failure of colonoscopies carried out during the audit period. Enable improvement in practise by highlighting poor practise and encouraging reflection. <h3>Audit Standards</h3> Caecal Intubation: &gt; 90%. Perforation rate: &lt; 1:1000 colonoscopies. <h3>Methods</h3> A retrospective search was made of the colonoscopy database of all colonoscopies performed on patients above the age of eighteen in UHL between September 2011 and September 2012. In addition a comparison was made between the colonoscopy database and patients presenting to UHL hospitals with a diagnosis of perforation. This was to identify late presentation of perforations potentially due to colonoscopies. The procedural notes were analysed looking for: Successful visualisation of the Caecum, Ileum/neo TI or anastomosis; reasons for failure, if applicable and complications. The results were then pooled and compared against the audit standard. <h3>Results</h3> 4001 colonoscopies were performed over the audit period. 3680 (92%) were successful. There were 80 complications (2%) in total. Most common complications were difficult intubation and patient distress with 52 (1.3%) and 16 (0.4%) instances respectively. 1 (0.02%) perforation occurred. Success rate over 5 years: 69% in 2006–2007, 89% in 2007–2008, 93% in 2010–2011 and 92% in 2011–2012. <h3>Conclusion</h3> Over the audit period UHL achieved its colonoscopy targets with a success rate of 92% and a perforation rate of 1 in 4001. Over the past five years the colonoscopy success rate has steadily improved from 69% in 2006–2007 to 92% in 2011–2012. Over the past two years UHL has achieved its target with success rates of 93% and 92% respectively. The results of each audit are reviewed by the endoscopy lead who meets people who have completion rates below the national average and also those who are doing less than a hundred and fifty colonoscopies a year. The aim of the meeting is to inform them of their performance and offer opportunities for improvement e.g. training. This shows the value of these audits in highlighting poor practise and prompting reflection and improvement. <h3>Disclosure of Interest</h3> None Declared <h3>References</h3> Gut. 2012 Jul; 61(7):1050–7. Epub 2011 Sep 22 Gastroenterology Volume 143, Issue 3, Pages 844–857, September 2012
Placental protein 13 (PP13): a new biological target shifting individualized risk assessment to personalized drug design combating pre-eclampsia
Authors: B. Huppertz, H. Meiri, S. Gizurarson, G. Osol, M. Sammar
Journal: Human Reproduction Update (2013)

Pre-eclampsia affects 2–7% of all pregnant women and is a major cause of maternal and fetal morbidity and mortality. The etiology of pre-eclampsia is still unknown but it is well documented that impaired placentation is a major contributor to its development. One of the placenta-specific proteins is placental protein 13 (PP13). Lower first trimester levels of maternal serum PP13 and its encoding placental mRNA are associated with the development of both early and late-onset severe pre-eclampsia. In cases where this protein is mutated, the frequency of pre-eclampsia is higher. 19 out of 68 studies on PP13, published between January 2006 and September 2012, were used to evaluate the value of maternal blood PP13 as a marker of pre-eclampsia. A meta-analysis presented in this review shows that low serum levels of PP13 in the first trimester of pregnancy can predict the development of pre-eclampsia later in pregnancy. Although some functions of this protein have been assessed in in vitro experiments, the in vivo functions of PP13 are still unknown, especially when circulating in the maternal bloodstream. A recent pilot study has shown that in gravid rats PP13 causes significant vasodilatation, reduced blood pressure and increased maternal uterine artery remodeling. Reviewing these effects of PP13, the authors propose the use of PP13 as a new drug candidate. Replenishing PP13 in those women with low serum levels early in pregnancy may help prepare their vasculature for pregnancy. This novel pharmacological approach to combat pre-eclampsia is presented as a new direction to transfer from individualized risk to personalized prevention.
Survivin Enhances Motility of Melanoma Cells by Supporting Akt Activation and α5 Integrin Upregulation
Authors: Jodi A. McKenzie, Tong Liu, Agnessa G. Goodson, Douglas Grossman
Journal: Cancer Research (2010)

Abstract Survivin expression in melanoma is inversely correlated with patient survival. Transgenic mice harboring melanocyte-specific overexpression of survivin exhibit increased susceptibility to UV-induced melanoma and metastatic progression. To understand the mechanistic basis for metastatic progression, we investigated the effects of survivin on the motility of human melanocytes and melanoma cells. We found that survivin overexpression enhanced migration on fibronectin and invasion through Matrigel, whereas survivin knockdown under subapoptotic conditions blocked migration and invasion. In melanocytes, survivin overexpression activated the Akt and mitogen-activated protein kinase pathways. Akt phosphorylation was required for survivin-enhanced migration and invasion, whereas Erk phosphorylation was required only for enhanced invasion. In both melanocytes and melanoma cells, survivin overexpression was associated with upregulation of α5 integrin (fibronectin receptor component), the antibody-mediated blockade or RNA interference-mediated knockdown of which blocked survivin-enhanced migration. Knockdown of α5 integrin did not affect Akt activation, but inhibition of Akt phosphorylation prevented α5 integrin upregulation elicited by survivin overexpression. Together, our results showed that survivin enhanced the migration and invasion of melanocytic cells and suggested that survivin may promote melanoma metastasis by supporting Akt-dependent upregulation of α5 integrin. Cancer Res; 70(20); 7927–37. ©2010 AACR.