tbuckley/cabot-search huggingface dataset:
ERK1/2 Blockade Prevents Epithelial–Mesenchymal Transition in Lung Cancer Cells and Promotes Their Sensitivity to EGFR Inhibition
Authors: Janine M. Buonato, Matthew J. Lazzara
Journal: Cancer Research (2013)

Overcoming cellular mechanisms of de novo and acquired resistance to drug therapy remains a central challenge in the clinical management of many cancers, including non-small cell lung cancer (NSCLC). Although much work has linked the epithelial-mesenchymal transition (EMT) in cancer cells to the emergence of drug resistance, it is less clear where tractable routes may exist to reverse or inhibit EMT as a strategy for drug sensitization. Here, we demonstrate that extracellular signal-regulated kinase (ERK) 1/2 (mitogen-activated protein kinase 3/1, MAPK3/1) signaling plays a key role in directing the mesenchymal character of NSCLC cells and that blocking ERK signaling is sufficient to heighten therapeutic responses to EGF receptor (EGFR) inhibitors. MEK1/2 (MAPKK1/2) inhibition promoted an epithelial phenotype in NSCLC cells, preventing induction of EMT by exogenous TGF-β. Moreover, in cells exhibiting de novo or acquired resistance to the EGFR inhibitor gefitinib, MEK inhibition enhanced the sensitivity to gefitinib and slowed cell migration. These effects only occurred, however, if MEK was inhibited for a period sufficient to trigger changes in EMT marker expression. Consistent with these findings, changes in EMT phenotypes and markers were also induced by the expression of mutant KRAS in a MEK-dependent manner. Our results suggest that prolonged exposure to MEK or ERK inhibitors may not only restrain EMT but also overcome naïve or acquired resistance of NSCLC to EGFR-targeted therapy in the clinic.
Influence of cholesteryl ester transfer protein, peroxisome proliferator–activated receptor α, apolipoprotein E, and apolipoprotein A-I polymorphisms on high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein A-I, and lipoprotein A-I:A-II concentrations: the Prospective Epidemiological Study of Myocardial Infarction study
Authors: Hong Quang Do, Hassan Nazih, Gérald Luc, Dominique Arveiler, Jean Ferrières, Alun Evans, Philippe Amouyel, François Cambien, Pierre Ducimetière, Jean-Marie Bard
Journal: Metabolism (2009)
Breast Cancer and Silicone Implants: Psychological Consequences for Women
Authors: C. Hatcher, L. Brooks, C. Love
Journal: JNCI Journal of the National Cancer Institute (1993)

One of every nine women in the United States is expected to develop breast cancer at some point in her lifetime. An estimated 180000 women are diagnosed with breast cancer each year (7-5). For many of these women, excision of the tumor, resulting in surgical modification of the breast, is the primary component of the treatment response. The U.S. Food and Drug Administration (FDA) (4) estimates that approximately 20% of these women elect breast implant surgery following mastectomy. The use of breast implants, particularly silicone implants, has generated considerable discussion in scientific forums, clinical treatment settings, lay consumer groups, legislatures, and regulatory agencies. Surgical insertion of breast implants dates back to the initial use of polyvinyl alcohol sponges (5). However, relatively few implant procedures were performed until the
Strong Time Dependence of the 76-Gene Prognostic Signature for Node-Negative Breast Cancer Patients in the TRANSBIG Multicenter Independent Validation Series
Authors: Christine Desmedt, Fanny Piette, Sherene Loi, Yixin Wang, Françoise Lallemand, Benjamin Haibe-Kains, Giuseppe Viale, Mauro Delorenzi, Yi Zhang, Mahasti Saghatchian d'Assignies, Jonas Bergh, Rosette Lidereau, Paul Ellis, Adrian L. Harris, Jan G.M. Klijn, John A. Foekens, Fatima Cardoso, Martine J. Piccart, Marc Buyse, Christos Sotiriou
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Recently, a 76-gene prognostic signature able to predict distant metastases in lymph node–negative (N−) breast cancer patients was reported. The aims of this study conducted by TRANSBIG were to independently validate these results and to compare the outcome with clinical risk assessment. Experimental Design: Gene expression profiling of frozen samples from 198 N− systemically untreated patients was done at the Bordet Institute, blinded to clinical data and independent of Veridex. Genomic risk was defined by Veridex, blinded to clinical data. Survival analyses, done by an independent statistician, were done with the genomic risk and adjusted for the clinical risk, defined by Adjuvant! Online. Results: The actual 5- and 10-year time to distant metastasis were 98% (88-100%) and 94% (83-98%), respectively, for the good profile group and 76% (68-82%) and 73% (65-79%), respectively, for the poor profile group. The actual 5- and 10-year overall survival were 98% (88-100%) and 87% (73-94%), respectively, for the good profile group and 84% (77-89%) and 72% (63-78%), respectively, for the poor profile group. We observed a strong time dependence of this signature, leading to an adjusted hazard ratio of 13.58 (1.85-99.63) and 8.20 (1.10-60.90) at 5 years and 5.11 (1.57-16.67) and 2.55 (1.07-6.10) at 10 years for time to distant metastasis and overall survival, respectively. Conclusion: This independent validation confirmed the performance of the 76-gene signature and adds to the growing evidence that gene expression signatures are of clinical relevance, especially for identifying patients at high risk of early distant metastases.
Abnormal Epicardial Coronary Resistance in Patients With Diffuse Atherosclerosis but “Normal” Coronary Angiography
Authors: Bernard De Bruyne, Ferry Hersbach, Nico H.J. Pijls, Jozef Bartunek, Jan-Willem Bech, Guy R. Heyndrickx, K. Lance Gould, William Wijns
Journal: Circulation (2001)

Background Coronary arteries without focal stenosis at angiography are generally considered non–flow-limiting. However, atherosclerosis is a diffuse process that often remains invisible at angiography. Accordingly, we hypothesized that in patients with coronary artery disease, nonstenotic coronary arteries induce a decrease in pressure along their length due to diffuse coronary atherosclerosis. Methods and Results Coronary pressure and fractional flow reserve (FFR), as indices of coronary conductance, were obtained from 37 arteries in 10 individuals without atherosclerosis (group I) and from 106 nonstenotic arteries in 62 patients with arteriographic stenoses in another coronary artery (group II). In group I, the pressure gradient between aorta and distal coronary artery was minimal at rest (1±1 mm Hg) and during maximal hyperemia (3±3 mm Hg). Corresponding values were significantly larger in group II (5±4 mm Hg and 10±8 mm Hg, respectively; both P &lt;0.001). The FFR was near unity (0.97±0.02; range, 0.92 to 1) in group I, indicating no resistance to flow in truly normal coronary arteries, but it was significantly lower (0.89±0.08; range, 0.69 to 1) in group II, indicating a higher resistance to flow. In 57% of arteries in group II, FFR was lower than the lowest value in group I. In 8% of arteries in group II, FFR was &lt;0.75, the threshold for inducible ischemia. Conclusion Diffuse coronary atherosclerosis without focal stenosis at angiography causes a graded, continuous pressure fall along arterial length. This resistance to flow contributes to myocardial ischemia and has consequences for decision-making during percutaneous coronary interventions.
Glutathione redox cycle enzymes and selenium in severe rheumatoid arthritis: lack of antioxidative response to selenium supplementation in polymorphonuclear leucocytes.
Authors: U Tarp, K Stengaard-Pedersen, J C Hansen, E B Thorling
Journal: Annals of the Rheumatic Diseases (1992)

The antioxidant capacity of the glutathione redox cycle and the concentrations of selenium in serum, red blood cells or whole blood, and polymorphonuclear leucocytes was evaluated in nine patients with severe rheumatoid arthritis (RA) and eight healthy controls receiving daily supplementation with 250 micrograms selenomethionine for six months. Serum and whole blood concentrations of selenium and the activity of the selenium dependent enzyme glutathione peroxidase (GSH-Px) were low in the serum, red blood cells, and polymorphonuclear leucocytes of patients with RA before selenium supplementation. During supplementation serum and whole blood concentrations of selenium and the activity of GSH-Px in serum and red blood cells of patients with RA and serum GSH-Px in controls increased. Selenium and GSH-Px in polymorphonuclear leucocytes were unaffected in patients with RA in contrast with the controls where both were augmented. Glutathione reductase activity in the red blood cells and polymorphonuclear leucocytes of patients with RA was low but increased during selenium supplementation. Whole blood concentrations of glutathione were slightly lower in patients with RA than controls and no difference in the content in polymorphonuclear leucocytes was found between the groups. The activity in red blood cells of glucose-6-phosphate dehydrogenase was high in patients with RA, indicating sufficient function of the hexose monophosphate pathway. The reduced antioxidant activity of the glutathione redox cycle in patients with severe RA was mainly due to the low availability of selenium. This was further supported by the response to selenium supplementation in serum and red blood cells. In the polymorphonuclear leucocytes, however, no biochemical effects of selenium supplementation were seen. This lack of antioxidative response could play a pathogenetic part in inflammation in patients with RA.
gespeR: a statistical model for deconvoluting off-target-confounded RNA interference screens
Authors: Fabian Schmich, Ewa Szczurek, Saskia Kreibich, Sabrina Dilling, Daniel Andritschke, Alain Casanova, Shyan Huey Low, Simone Eicher, Simone Muntwiler, Mario Emmenlauer, Pauli Rämö, Raquel Conde-Alvarez, Christian von Mering, Wolf-Dietrich Hardt, Christoph Dehio, Niko Beerenwinkel
Journal: Genome biology (2015)

Small interfering RNAs (siRNAs) exhibit strong off-target effects, which confound the gene-level interpretation of RNA interference screens and thus limit their utility for functional genomics studies. Here, we present gespeR, a statistical model for reconstructing individual, gene-specific phenotypes. Using 115,878 siRNAs, single and pooled, from three companies in three pathogen infection screens, we demonstrate that deconvolution of image-based phenotypes substantially improves the reproducibility between independent siRNA sets targeting the same genes. Genes selected and prioritized by gespeR are validated and shown to constitute biologically relevant components of pathogen entry mechanisms and TGF-β signaling. gespeR is available as a Bioconductor R-package.
Survival Advantage of EBV-Associated Gastric Carcinoma: Survivin Up-regulation by Viral Latent Membrane Protein 2A
Authors: Rumi Hino, Hiroshi Uozaki, Yoko Inoue, Yukako Shintani, Tetsuo Ushiku, Takashi Sakatani, Kenzo Takada, Masashi Fukayama
Journal: Cancer Research (2008)

Abstract EBV-associated gastric carcinoma is a distinct subset of gastric carcinoma infected with EBV, which shows latency I type expression of EBV latent genes (EBNA1, EBER, BARF0, and LMP2A). To clarify the role of EBV in this type of gastric carcinoma, the cell biological characteristics (growth, apoptosis, and migration) were evaluated in gastric carcinoma cell lines (MKN-1, TMK1, MKN-74 and MKN-7) with and without infection of recombinant EBV harboring the neomycin resistance gene. The infection reiterated the latency I type infection, and the only difference observed in EBV-infected gastric carcinoma cell lines was the resistance to serum deprivation–induced apoptosis. Comparative analyses of transcripts of apoptosis-associated genes in MKN-1 and EBV–MKN-1 and subsequent quantitative reverse transcription-PCR analysis showed up-regulation of the cellular survivin gene in EBV-infected gastric carcinoma cell lines. Small interfering RNA–mediated knockdown of survivin increased apoptosis in EBV–MKN-1 to the level of the original MKN-1 cells. Transfection of EBV-latent genes into MKN-1 showed that LMP2A, but not EBNA1, EBER, or BARF0, up-regulated survivin gene expression. LMP2A-mediated survivin up-regulation in gastric carcinoma cells was inhibited with a nuclear factor-κB (NF-κB) inhibitor, Bay 11-7082. In parallel with these findings in vitro, survivin expression was frequent in carcinoma tissues of gastric carcinoma by immunohistochemistry, and significantly more in EBV-associated gastric carcinoma (12 of 13) than in EBV-negative gastric carcinoma in the advanced stage (P = 0.0307). Thus, EBV uses its latent protein, LMP2A, to activate the NF-κB–survivin pathway to rescue EBV-infected epithelial cells from serum deprivation, and up-regulation of survivin may play a role in the progression of this specific type of gastric carcinoma infected with EBV. [Cancer Res 2008;68(5):1427–35]
Studies on the plasma membrane of normal and psoriatic keratinocytes.
Authors: J.M. GOMMANS, MIEKE BERGERS, P.E.J. ERP, JOSE J.M.A. HURK, P.D. MIER, H. ROELFZEMA
Journal: British Journal of Dermatology (1979)

A method is described for the preparation of isolated keratinocytes suitable for subsequent biochemical studies. Scanning electron microscopy showed that the maturation process is accompanied by an increase in cell size and a shortening and eventual loss of microvilli. Psoriatic keratinocytes are distinguishable by exhibiting longer microvilli at all levels of maturation.
Slow Conduction in Cardiac Tissue, I
Authors: Stephan Rohr, Jan P. Kucera, André G. Kléber
Journal: Circulation Research (1998)

Abstract —It was the aim of this study to characterize the spread of activation at the cellular level in cardiac tissue during conduction slowing, a key element of reentrant arrhythmias; therefore, activation patterns were assessed at high spatiotemporal resolution in narrow (70 to 80 μm) and wide (230 to 270 μm) linear strands of cultured neonatal rat ventricular myocytes, using multiple site optical recording of transmembrane voltage. Slow conduction was induced by graded elevation of [K + ] o , by applying tetrodotoxin, or by exposing the preparations to the gap junctional uncouplers palmitoleic acid or 1-octanol. The main findings of the study are 4-fold: (1) gap junctional uncoupling reduced conduction velocity (range, 37 to 47 cm/s under control conditions) to a substantially larger extent before block (≤1 cm/s; ultra-slow conduction) than did a reduction of excitability (range, ≈10 to 15 cm/s); (2) activation wavefronts during uncoupling meandered within the boundaries of the preparations, resulting in a pronounced additional slowing of conduction in wide cell strands; (3) at the cellular level, propagation during uncoupling-induced ultra-slow conduction was sustained by sequentially activated tissue patches, each of which consisted of a few cells being activated simultaneously; and (4) depending on the uncoupler used, maximal action potential upstroke velocities during ultra-slow conduction were either slightly (palmitoleic acid) or highly (1-octanol) depressed. Thus, depolarizing inward currents, the spatial pattern and degree of gap junctional coupling, and geometrical factors all contribute in a concerted manner to conduction slowing, which, at its extreme (0.25 cm/s measured over 1 mm), can reach values low enough to permit, theoretically, reentrant excitation to occur in minuscule areas of cardiac tissue (≪1 mm 2 ).
Studies on the purification of antihemophilic factor (factor VIII)
Authors: Lawrence Kass, Oscar D. Ratnoff, Myron A. Leon
Journal: Journal of Clinical Investigation (1969)

Concanavalin A precipitates antihemophilic factor from normal plasma. Combining this precipitation with other techniques, we were able to separate fractions rich in antihemophilic activity from human plasma with rapidity. The molecular weight of antihemophilic factor was estimated to be greater than 2 million. Presumably, antihemophilic factor is a large glycoprotein.
Sarcoidosis in the Bantu.
Authors: J.G.L. MORRISON
Journal: British Journal of Dermatology (1974)

Sarcoidosis in the Bantu differs from the same condition in other populations mainly in the severity and the more destructive nature of the lesions. Localization, immune responses and treatment yield similar findings to those met with elsewhere, but necrosis within the granulomata may be prominent and deforming.
Genotoxicity of Acrylamide and Glycidamide
Authors: Ahmad Besaratinia, Gerd P Pfeifer
Journal: JNCI Journal of the National Cancer Institute (2004)

Acrylamide, a known rodent carcinogen, is found in the human diet. However, the mechanism by which acrylamide exerts its carcinogenic effects remains unclear.Normal human bronchial epithelial cells and Big Blue mouse embryonic fibroblasts that carry a lambda phage cII transgene were treated in vitro with acrylamide, its primary epoxide metabolite glycidamide, or water (control) and then subjected to terminal transferase-dependent polymerase chain reaction to map the formation of DNA adducts within the human gene encoding p53 (TP53) and the cII transgene. The frequency and spectrum of glycidamide-induced mutations in cII were examined by using a lambda phage-based mutation detection system and DNA sequence analysis, respectively. All statistical tests were two-sided.Acrylamide and glycidamide formed DNA adducts at similar specific locations within TP53 and cII, and DNA adduct formation was more pronounced after glycidamide treatment than after acrylamide treatment at all doses tested. Acrylamide-DNA adduct formation was saturable, whereas the formation of most glycidamide-DNA adducts was dose-dependent. Glycidamide treatment dose-dependently increased the frequency of cII mutations relative to control treatment (P<.001). Glycidamide was more mutagenic than acrylamide at any given dose. The spectrum of glycidamide-induced cII mutations was statistically significantly different from the spectrum of spontaneously occurring mutations in the control-treated cells (P=.038). Compared with spontaneous mutations in control cells, cells treated with glycidamide or acrylamide had more A-->G transitions and G-->C transversions and glycidamide-treated cells had more G-->T transversions (P<.001).The mutagenicity of acrylamide in human and mouse cells is based on the capacity of its epoxide metabolite glycidamide to form DNA adducts.
Common Genomic Response in Different Mouse Models of β-Adrenergic–Induced Cardiomyopathy
Authors: Vinciane Gaussin, James E. Tomlinson, Christophe Depre, Stefan Engelhardt, Christopher L. Antos, Gen Takagi, Lutz Hein, James N. Topper, Stephen B. Liggett, Eric N. Olson, Martin J. Lohse, Stephen F. Vatner, Dorothy E. Vatner
Journal: Circulation (2003)

Although beta-adrenergic receptor (AR) blockade therapy is beneficial in the treatment of heart failure, little is known regarding the transcriptional mechanisms underlying this salutary action.In the present study, we screened mice overexpressing Gsalpha, beta1AR, beta2AR, or protein kinase A to test if a common genomic pathway exists in different models with enhanced beta-adrenergic signaling. In mice overexpressing Gsalpha, differentially expressed genes were identified by mRNA profiling. In addition to well-known markers of cardiac hypertrophy (atrial natriuretic factor, CARP, and beta-myosin heavy chain), uncoupling protein 2 (UCP2), a protein involved in the control of mitochondrial membrane potential, and four-and-a-half LIM domain protein-1 (FHL1), a member of the LIM protein family, were predicted to be upregulated. Upregulation of these genes was confirmed by quantitative reverse transcriptase-polymerase chain reaction at all time points tested during the development of cardiomyopathy in mice overexpressing Gsalpha. In mice overexpressing beta1AR, beta2AR, or protein kinase A, increased UCP2 and FHL1 expression was also observed at the onset of cardiomyopathy. BetaAR blockade treatment reversed the cardiomyopathy and suppressed the increased expression of UCP2 and FHL1 in mice overexpressing Gsalpha.UCP2 and FHL1 are important candidate genes that correlate with the development of betaAR-induced cardiomyopathy in different mouse models with enhanced betaAR signaling. In addition to preserving cardiac function, betaAR blockade treatment also prevents the genomic regulation that correlates with the onset of heart failure.
Busulfan Treatment During Pregnancy
Authors: J. Pinto Machado
Journal: JAMA (1967)

<h3>To the Editor:—</h3> In "Busulfan Treatment of Leukemia During Pregnancy" (<b>199</b>:131, 1967), Dugdale and Fort conclude, "Busulfan when used alone and in the usual dosage is not toxic to the human fetus." This conclusion is based upon two facts: (1) In all instances (ten cases) in which busulfan was the sole antileukemic agent used during pregnancy, the infants were apparently normal (although three were small). (2) The single dose that, administered to the rat, produces sterility in both male and female offspring<sup>1</sup>is considerably higher than the daily doses used clinically; even the total dose is less in most patients. The authors noted, without comments, the report of Diamond, et al<sup>2</sup>concerning an infant with ovarian aplasia whose mother took mercaptopurine and busulfan during pregnancy. It is possible that the conclusion of Dugdale and Fort is right, but I think that their arguments are questionable. We cannot
Differences in proteins synthesized by fibroblasts from normal individuals and patients with complete testicular feminization.
Authors: G P Risbridger, B A Khalid, G L Warne, J W Funder
Journal: Journal of Clinical Investigation (1982)

Patterns of protein synthesis by genital skin fibroblasts from three unrelated normal individuals and three unrelated patients with complete testicular feminization were compared to two-dimensional gel electrophoresis. cell lines were maintained in monolayer culture and pulse labeled with [35S]methionine. Cells were lysed in 9 M urea, and aliquots of 20 microliters subjected to isoelectric focussing and polyacrylamide gel electrophoresis followed by autoradiography. Gels of control fibroblasts showed two proteins (mol wt approximately 45,000, approximately 85,000; pKi approximately 5.0) markedly more prominent than on gels from affected fibroblasts. This pattern was unaltered by prior exposure to dihydrotestosterone, suggesting differences in constitutive proteins of the fibroblast cells. Parallel studies demonstrated a marked reduction in the ability of fibroblasts from patients with complete testicular feminization to bind androgens in vitro compared with those of normal individuals. The relationship between these proteins, androgen receptors, and androgen insensitivity requires further investigation.
Influence of Infant Gut Microbiome on Development of Infant Regulatory T Cells
Authors: Kevin Bobbitt, Albert M. Levin, Suzanne Havstad, Alexandra R. Sitarik, Kei Fujimura, Kimberley J. Woodcroft, Ganesa R. Wegienka, Edward M. Zoratti, Andrea Cassidy-Bushrow, Haejin Kim, Homer A. Boushey, Dennis Ownby, Christine Cole Johnson, Nicholas W. Lukacs, Susan V. Lynch
Journal: Journal of Allergy and Clinical Immunology (2015)