tbuckley/cabot-search huggingface dataset:
Prognostic Impact of Alterations in P-Cadherin Expression and Related Cell Adhesion Markers in Endometrial Cancer
Authors: Ingunn M. Stefansson, Helga B. Salvesen, Lars A. Akslen
Journal: Journal of Clinical Oncology (2004)

Purpose Reduced tumor cell adhesion is associated with invasive growth and unfavorable prognosis. In endometrial carcinoma, the prognostic impact of adhesion markers (E-cadherin, beta-catenin [β-catenin], P-cadherin, and p120 ctn ) is partly unknown. We wanted to examine the expression pattern and prognostic value of these molecules in a population-based series of endometrial carcinoma patients. Patients and Methods All patients diagnosed with endometrial carcinoma between 1981 and 1990 in Hordaland County, Norway, were included. Paraffin-embedded tumor tissue was available for 96% of the patients (n = 286), and was studied immunohistochemically for expression of E-cadherin, β-catenin, P-cadherin, and p120 ctn . The tissue microarray technique was used for P-cadherin and p120 ctn . Median follow-up time for survivors was 9 years (range, 4 to 16 years) and follow-up was complete. Results Pathologic expression of P-cadherin, E-cadherin, and β-catenin was associated with a majority of the clinicopathologic variables. In univariate survival analyses, all adhesion markers influenced survival significantly (P &lt; .05). Tumors with pathologic expression of both E-cadherin (low expression) and P-cadherin (high expression; 19%), and β-catenin (low expression) and P-cadherin (high expression; 16%), had significantly reduced survival compared with the remaining samples (P &lt; .001 for both). In multivariate models, all markers except E-cadherin showed independent prognostic significance in addition to the traditional tumor features. Conclusion Differential expression of P-cadherin and β-catenin seems to be important in endometrial carcinoma and is associated with aggressive subgroups. Our findings also indicate that a shift from E-cadherin to P-cadherin expression (cadherin switch) is an important prognostic feature in these tumors.
Abstract B17: The small RhoGTPase RhoB as a new potential marker of EGFR-TKI resistance
Authors: Claire Marty, Gilles Favre, Julien Mazieres
Journal: Clinical Cancer Research (2012)

Abstract Introduction: EGFR tyrosine kinase inhibitors (EGFR-TKI) are widely used in metastatic non small cell lung cancer (NSCLC). Nevertheless, the majority of patients with wild type EGFR do not respond to these treatments and, in the selected group with EGFR mutations, we some primary resistance and all the patients will ultimately develop acquired resistance. The small RHO GTPase RhoB is involved in cell proliferation, invasion, apoptosis and can act as a tumor suppressor gene in lung carcinogenesis by controlling survival and invasion through AKT pathway. Furthermore, RhoB participates in the regulation of endocytic trafficking of EGFR. Specifically, activated RhoB is able to delay the transport of internalized EGFR to lysosomes, thus modifying its downstream signaling. The objective of our study is to know if RhoB is a molecular determinant of the response to the EGFR-TKI erlotinib, and if RhoB could be a marker for erlotinib resistance. Material and Method: We used various lung cancer cell lines harboring either wild-type or mautated EGFR and K-Ras. RhoB was either overexpressed by adenovirus transfection or inhibited by interfering RNA (siRNA) in these cells. Cell proliferation after 72h of treatment with erlotinib was measured by a colorimetric assay. In the same way, we performed invasion assays and western-blot analyses of downtsream signaling pathways. Results: (1) RhoB overexpression decreases the sensitivity to erlotinib of cells presenting a wild type or mutated EGFR in a dose-dependent manner whereas the sensitivity to erlotinib of cells bearing KRas mutation was not affected by RhoB overexpression. (2) Erlotinib-induced inhibition of cellular invasion is impaired by overexpression of RhoB in wild type or mutated EGFR cell lines. (3) The phosphorylation of Akt (and not of ERK) is inhibited by erlotinib and is restored upon overexpression of RhoB invasion. Conclusions: Our results suggest that RhoB is involved in the sensitivity to erlotinib in wild-type K-Ras cells harboring either mutated or wild-type EGFR. RhoB is able to block erlotinib-induced inhibition of cell proliferation and invasion mainly through AKT pathway modulation. We plan to extend our in vitro findings in a cohort of patients treated with erlotinib.
Mutation discovery in mice by whole exome sequencing
Authors: Heather Fairfield, Griffith J Gilbert, Mary Barter, Rebecca R Corrigan, Michelle Curtain, Yueming Ding, Mark D'Ascenzo, Daniel J Gerhardt, Chao He, Wenhui Huang, Todd Richmond, Lucy Rowe, Frank J Probst, David E Bergstrom, Stephen A Murray, Carol Bult, Joel Richardson, Benjamin T Kile, Ivo Gut, Jorg Hager, Snaevar Sigurdsson, Evan Mauceli, Federica Di Palma, Kerstin Lindblad-Toh, Michael L Cunningham, Timothy C Cox, Monica J Justice, Mona S Spector, Scott W Lowe, Thomas Albert, Leah Rae Donahue, Jeffrey Jeddeloh, Jay Shendure, Laura G Reinholdt
Journal: Genome biology (2011)

We report the development and optimization of reagents for in-solution, hybridization-based capture of the mouse exome. By validating this approach in a multiple inbred strains and in novel mutant strains, we show that whole exome sequencing is a robust approach for discovery of putative mutations, irrespective of strain background. We found strong candidate mutations for the majority of mutant exomes sequenced, including new models of orofacial clefting, urogenital dysmorphology, kyphosis and autoimmune hepatitis.
Does psychosocial stress play a role in the exacerbation of psoriasis?
Authors: H.J.A. Hunter, C.E.M. Griffiths, C.E. Kleyn
Journal: British Journal of Dermatology (2013)

It is widely accepted that psychosocial stress can result from the daily strains of living with a diagnosis of psoriasis. There is now an evolving body of work to suggest that psychosocial stress may also play a role in the exacerbation of psoriasis. We discuss the historical evidence supporting a temporal relationship between psychosocial stress and the exacerbation of psoriasis. The underlying pathophysiological mechanisms by which this occurs are largely unknown, but current evidence points towards a role for nerve-related factors, namely their interaction with mast cells and the potentiation of neurogenic inflammation in this regard. It is also likely that the physiological stress response in patients with psoriasis differs from that in healthy individuals, as evidenced by alterations in the hypothalamic-pituitary-adrenal axis and sympathetic-adrenal-medullary system function. Psychological stress results in a redistribution of leucocytes with increased trafficking of inflammatory cells into the skin, which may exacerbate psoriasis. Langerhans cells play a role in the stress response of normal skin; their function in the stress response of patients with psoriasis is open to speculation. We discuss the influence of stress reactivity in patients with psoriasis and the impact of stress reduction strategies in the management of psoriasis. Finally, we suggest potentially fruitful areas for future research.
Miniaturization of the organ care system® into rat lungs for the establishment of ex-vivo therapy
Authors: Bettina Wiegmann, Danny Jonigk, Peter Braubach, Klaus Höffler, Siegfried Bachmann, Julia Weder, Anatol Ciubutaro, Axel Haverich
Journal: European Respiratory Journal (2014)

Objectives

Organ Care System® (OCS) is a well-established system used in human lung transplantation, allowing warm perfusion and ventilation of donor lungs. Besides lung retrieval, OCS therefore offers an innovative opportunity for clinical ex-vivo therapy of diseased lungs for different indications, e. g. tumor therapy. While the patient is on extracorporeal membrane oxygenation, the otherwise inoperable lungs can be treated in OCS, followed by autotransplantation. For the development of this ex-vivo therapy, a miniaturized OCS was established.

Methods

Wistar rats were euthanized (per group n=5), left lungs were connected to OCS, while right lungs were stored on ice. OCS lungs were ventilated and perfused at body temperature under continuous monitoring (e. g. pressure). Four different perfusion solutions were analyzed (Steen solution® ± blood, OCS solution® ± blood). Finally lungs were processed histopathologically.

Results

OCS worked technically faultless, perfusion and ventilation went well. All perfusion solutions showed stable pH, pO2, pCO2, oncotic pressure and systemic pressure. Using perfusion solutions combined with blood, lactate levels increased up to 7,0mmol/l and base excess has to be stabilized by sodium hydrogen carbonate. Pathological work up revealed no significant morphological changes, except for focal atelectasis. There were no delimitable differences between the examined groups.

Conclusions

The miniaturized OCS is a reliably working system to establish the ex-vivo therapies for different indiations. As ex-vivo therapies may need to be applied for more than 4 hours, extended perfusion times and various perfusion solutions are currently investigated.
Ara h 8, a Bet v 1–homologous allergen from peanut, is a major allergen in patients with combined birch pollen and peanut allergy
Authors: Diana Mittag, Jaap Akkerdaas, Barbara K. Ballmer-Weber, Lothar Vogel, Marjolein Wensing, Wolf-Meinhard Becker, Stef J. Koppelman, André C. Knulst, Arthur Helbling, Susan L. Hefle, Ronald van Ree, Stefan Vieths
Journal: Journal of Allergy and Clinical Immunology (2004)
Mitochondrial antiviral signaling protein defect links impaired antiviral response and liver injury in steatohepatitis in mice
Authors: Timea Csak, Angela Dolganiuc, Karen Kodys, Bharath Nath, Jan Petrasek, Shashi Bala, Dora Lippai, Gyongyi Szabo
Journal: Hepatology (2011)

Mitochondrial dysfunction is a pathogenic feature of nonalcoholic steatohepatitis (NASH). NASH complicates hepatotropic viral disease. The mitochondrial antiviral signaling protein (MAVS) is the adapter of helicase receptors involved in sensing double-stranded RNA (dsRNA). We hypothesized that impaired MAVS function may contribute to insufficient antiviral response and liver damage in steatohepatitis. We identified reduced MAVS protein levels and increased MAVS association with the proteasome subunit alpha type 7 (PSMA7) in livers from mice given a methionine-choline-deficient (MCD) diet. Decreased association of MAVS with mitochondria and increased cytosolic cytochrome c indicated mitochondrial damage in steatohepatitis. In vivo administration of the synthetic dsRNA polyinosinic:polycytidylic acid [poly(I:C)], but not lipopolysaccharide or cytidine-phosphate-guanosine-rich DNA, resulted in impaired induction of type I interferons (IFNs) and proinflammatory cytokines in steatohepatitis. Consistent with a defect in helicase receptor-induced signaling, there was loss of poly(I:C)-induced translocation of MAVS to the cytosol and decreased IFN regulatory factor 3 phosphorylation. Caspases 1 and 8, both of which cleave MAVS, were increased in MCD diet-fed mice. At baseline, steatohepatitis was associated with increased serum alanine aminotransferase (ALT), apoptosis and caspase 3 activation compared with controls. In contrast to apoptosis in controls, necrosis was induced by poly(I:C) stimulation in steatohepatitis. Hepatocyte necrosis was indicated by elevated serum high-mobility group box protein-1 and ALT and was correlated with increased expression of receptor-interacting protein 3 (RIP3), a master regulator of necrosis. Increased expression of MAVS, PSMA7, and RIP3 messenger RNA was also present in human NASH livers.Our novel findings suggest that mitochondrial damage in steatohepatitis extends to MAVS, an adapter of helicase receptors, resulting in inefficient type I IFN and inflammatory cytokine response but increased hepatocyte necrosis and RIP3 induction in response to a dsRNA viral challenge. These mechanisms may contribute to progressive liver damage and impaired viral clearance in NASH.
Histone Deacetylase Inhibitor Valproic Acid Enhances the Cytokine-Induced Expansion of Human Hematopoietic Stem Cells
Authors: Lidia De Felice, Caterina Tatarelli, Maria Grazia Mascolo, Chiara Gregorj, Francesca Agostini, Roberto Fiorini, Vania Gelmetti, Simona Pascale, Fabrizio Padula, Maria Teresa Petrucci, William Arcese, Clara Nervi
Journal: Cancer Research (2005)

Abstract Ex vivo amplification of human hematopoietic stem cells (HSC) without loss of their self-renewing potential represents an important target for transplantation, gene and cellular therapies. Valproic acid is a safe and widely used neurologic agent that acts as a potent inhibitor of histone deacetylase activities. Here, we show that valproic acid addition to liquid cultures of human CD34+ cells isolated from cord blood, mobilized peripheral blood, and bone marrow strongly enhances the ex vivo expansion potential of different cytokine cocktails as shown by morphologic, cytochemical, immunophenotypical, clonogenic, and gene expression analyses. Notably, valproic acid highly preserves the CD34 positivity after 1 week (range, 40-89%) or 3 weeks (range, 21-52%) amplification cultures with two (Flt3L + thrombopoietin) or four cytokines (Flt3L + thrombopoietin + stem cell factor + interleukin 3). Moreover, valproic acid treatment increases histone H4 acetylation levels at specific regulatory sites on HOXB4, a transcription factor gene with a key role in the regulation of HSC self-renewal and AC133, a recognized marker gene for stem cell populations. Overall, our results relate the changes induced by valproic acid on chromatin accessibility with the enhancement of the cytokine effect on the maintenance and expansion of a primitive hematopoietic stem cell population. These findings underscore the potentiality of novel epigenetic approaches to modify HSC fate in vitro.
Mechanisms by which SCN5A mutation N1325S causes cardiac arrhythmias and sudden death in vivo
Authors: X Tian
Journal: Cardiovascular Research (2003)

Objective: Mutations in the cardiac sodium channel gene SCN5A are responsible for type-3 long QT disease (LQT3). The genesis of cardiac arrhythmias in LQT3 is multifaceted, and the aim of this study was to further explore mechanisms by which SCN5A mutations lead to arrhythmogenesis in vivo. Methods: We engineered selective cardiac expression of a long QT syndrome (LQTS) mutation (N1325S) in human SCN5A and generated a transgenic mouse model, TGM(NS31). Results: Conscious and unrestrained TGM(NS31)L12 mice demonstrated a significant prolongation of the QT-interval and a high incidence of spontaneous polymorphic ventricular tachycardia (VT) and fibrillation (VF), often resulting in sudden cardiac death (n = 52:156). Arrhythmias were suppressed by mexiletine, a sodium channel blocker for the late persistent sodium current. Action potentials (APs) from TGM(NS31)L12 ventricular myocytes exhibited early afterdepolarizations and longer 90% AP durations (APD90=69±5.9 ms) than control (APD90=46.7±4.8 ms). Voltage-clamp experiments in transgenic myocytes revealed a peak inward sodium current (INa) followed by a slow recovery from inactivation. After mexiletine application, transgenic ventricular APDs were shortened, and recovery from inactivation of INa was enhanced. These suggest that the N1325S transgene is responsible for the abnormal signals present in transgenic cells as well as the genesis of lethal arrhythmias in mice. Interestingly, transgenic but not wild-type myocytes displayed longer APDs with a shortening of CLs. Conclusions: Our findings show that a new model for LQTS has been established, and we report on an arrhythmogenic mechanism that, unlike other SCN5A mutations, results in poor restitution of APD with increasing rate as a possible substrate for arrhythmogenesis.
The Effects of the Pro12Ala Polymorphism of the Peroxisome Proliferator-Activated Receptor- 2 Gene on Glucose/Insulin Metabolism Interact With Prenatal Exposure to Famine
Authors: S. R. de Rooij
Journal: Diabetes Care (2006)

An adverse fetal environment may permanently modify the effects of specific genes on glucose tolerance, insulin secretion, and insulin sensitivity. In the present study, we assessed a possible interaction of the peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala polymorphism with prenatal exposure to famine on glucose and insulin metabolism.We measured plasma glucose and insulin concentrations after an oral glucose tolerance test and determined the PPAR-gamma2 genotype among 675 term singletons born around the time of the 1944-1945 Dutch famine.A significant interaction effect between exposure to famine during midgestation and the PPAR-gamma2 Pro12Ala polymorphism was found on the prevalence of impaired glucose tolerance and type 2 diabetes. The Ala allele of the PPAR-gamma2 gene was associated with a higher prevalence of impaired glucose tolerance and type 2 diabetes but only in participants who had been prenatally exposed to famine during midgestation. Similar interactions were found for area under the curve for insulin and insulin increment ratio, which were lower for Ala carriers exposed to famine during midgestation.The effects of the PPAR-gamma2 Pro12Ala polymorphism on glucose and insulin metabolism may be modified by prenatal exposure to famine during midgestation. This is possibly due to a combined deficit in insulin secretion, as conferred by pancreatic beta-cell maldevelopment and carrier type of the Ala allele in the PPAR-gamma2 gene.
Integration of Embryonic Stem Cells in Metanephric Kidney Organ Culture
Authors: Brooke M. Steenhard, Kathryn S. Isom, Patricia Cazcarro, Judy H. Dunmore, Alan R. Godwin, Patricia L. St. John, Dale R. Abrahamson
Journal: Journal of the American Society of Nephrology (2005)

Many stages of nephrogenesis can be studied using cultured embryonic kidneys, but there is no efficient technique available to readily knockdown or overexpress transgenes for rapid evaluation of resulting phenotypes. Embryonic stem (ES) cells have unlimited developmental potential and can be manipulated at the molecular genetic level by a variety of methods. The aim of this study was to determine if ES cells could respond to developmental signals within the mouse embryonic day 12 to embryonic day 13 (E12 to E13) kidney microenvironment and incorporate into kidney structures. ROSA26 ES cells were shown to express beta-galactosidase ubiquitously when cultured in the presence of leukemia inhibitory factor to suppress differentiation. When these cells were microinjected into E12 to E13 metanephroi and then placed in transwell organ culture, ES cell-derived, beta-galactosidase-positive cells were identified in epithelial structures resembling tubules. On rare occasions, individual ES cells were observed in structures resembling glomerular tufts. Electron microscopy showed that the ES cell-derived tubules were surrounded by basement membrane and had apical microvilli and junctional complexes. Marker analysis revealed that a subset of these epithelial tubules bound Lotus tetragonolobus and expressed alpha(1) Na(+)/K(+) ATPase. ES cells were infected before injection with a cytomegalovirus promoter-green fluorescence protein (GFP) adenovirus and GFP expression was found as early as 18 h, persisting for up to 48 h in cultured kidneys. This ES cell technology may achieve the objective of obtaining a versatile cell culture system in which molecular interventions can be used in vitro and consequences of these perturbations on the normal kidney development program in vivo can be studied.
If Your Uneaten Food Moves, Take It to a Doctor
Authors: C. Darrell Lane
Journal: JAMA (1988)

<h3>To the Editor.—</h3> Anisakiasis is a common nematode parasitic disease of sea and saltwater-bay creatures present in both Atlantic and Pacific waters.<sup>1</sup>Humans who eat raw or inadequately cooked shellfish and other fish infested with this parasite may become infected. There is no simple, reliable, or economically practical method to eliminate contaminated seafood from the food supply. Heretofore, this has been an inconsequential problem, since adequate cooking (raising the temperature to 60°C for five minutes) kills the larvae, making the food safe for consumption.<sup>2</sup>But the recent proliferation of sushi bars and the increased popularity of uncommon foods containing raw fish as an ingredient have further focused attention on this infrequently diagnosed disease.<sup>2,3</sup> <h3>Report of a Case.—</h3> In January 1988, a housewife prepared locally purchased haddock in a new microwave oven. The woman and her son each consumed portions of the fish, while the remaining third portion
Distinct Molecular and Morphogenetic Properties of Mutations in the Human HNF1β Gene That Lead to Defective Kidney Development
Authors: Silvia Bohn, Heike Thomas, Gülüzar Turan, Sian Ellard, Coralie Bingham, Andrew T. Hattersley, Gerhart U. Ryffel
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. The homeobox transcription factor hepatocyte nuclear factor 1β (HNF1β) is a tissue-specific regulator that plays an essential role in early vertebrate development. In humans, heterozygous mutations in the HNF1β gene are associated with young-onset diabetes as well as a variety of disorders of renal development with cysts as the most consistent feature. This report compares and classifies nine different HNF1β mutations that lead in humans to distinct renal diseases, including solitary functioning kidney, renal dysplasia, glomerulocystic kidney disease, and oligomeganephronia. Analysis of these mutants in vitro identifies mutants that either retain or lack DNA binding. Investigation of the transactivation potential in transfected cell lines reveals a strict correlation between DNA binding and transactivation. Introduction of these mutants into developing Xenopus embryos shows that these mutants interfere with pronephros development, the first kidney form in amphibian. Whereas three mutants lead in Xenopus to a reduction or agenesis of the pronephric tubules and the anterior part of the duct, six mutants generate an enlargement of the pronephric structures. The differential morphogenetic potential in the developing embryo does not strictly correlate with the properties observed in vitro or in transfected cell lines. This suggests that the functional test in the developing embryo defines features of the HNF1β protein that cannot be assessed in cell cultures. The distinct properties observed in the various HNF1β mutants may guide the classification of the phenotypes observed in patients with a mutated HNF1β gene. E-mail: [email protected]
Subsequent Pregnancy After Gestational Diabetes Mellitus
Authors: Soo Heon Kwak, Hae Sung Kim, Sung Hee Choi, Soo Lim, Young Min Cho, Kyong Soo Park, Hak C. Jang, Moon Young Kim, Nam H. Cho, Boyd E. Metzger
Journal: Diabetes Care (2008)

The purpose of this study was to determine the frequency of recurrent gestational diabetes mellitus (GDM) and to find risk factors that can predict the recurrence of GDM in Korean women with previous GDM.We evaluated women who had GDM in an index pregnancy (1993-2001) and a subsequent pregnancy by 2003. An oral glucose tolerance test (OGTT) was performed during the index pregnancy and 2 months postpartum. The recurrence rate of GDM was assessed among 111 women who had a subsequent pregnancy. Multivariate logistic regression analysis was used to identify independent predictors of recurrent GDM.The frequency of recurrent GDM in subsequent pregnancies was 45.0% (95% CI 35.6-54.4%). Women with impaired fasting glucose and/or impaired glucose tolerance 2 months postpartum were at increased risk for recurrent GDM (relative risk 2.31, 95% CI 1.24-4.30). Higher BMI before the subsequent pregnancy (P = 0.024), higher fasting glucose concentration (P = 0.007) 2 months postpartum, and lower 1-h insulin concentration (P = 0.004) of the diagnostic OGTT in the index pregnancy were independent risk factors for recurrence of GDM in subsequent pregnancies.GDM recurred in nearly half of subsequent pregnancies in Korean women. Fasting glucose 2 months postpartum might be a clinically valuable predictor of recurrent GDM risk.