tbuckley/cabot-search huggingface dataset:
Antiangiogenic Antithrombin Induces Global Changes in the Gene Expression Profile of Endothelial Cells
Authors: Weiqing Zhang, Yung-Jen Chuang, Tianquan Jin, Richard Swanson, Yan Xiong, Lawrence Leung, Steven T. Olson
Journal: Cancer Research (2006)

Abstract Antithrombin, a serpin family protease inhibitor crucial to hemostasis, acquires antiangiogenic properties on undergoing conformational alterations induced by limited proteolysis or elevated temperature. To better understand the biochemical mechanisms underlying antithrombin antiangiogenic activity, we did genome-wide expression profiling, coupled with quantitative reverse transcription-PCR, Northern blot, and Western blot analyses, to characterize the gene expression patterns that are induced by antiangiogenic antithrombin in cultured primary human umbilical vein endothelial cells. Overall, 35 genes with significantly increased expression and 93 genes with significantly reduced expression (≥2-fold changes) due to antiangiogenic antithrombin treatment were identified. More than half of the down-regulated genes have well-established proangiogenic functions in endothelial cells, including cell-surface and matrix proteoglycans (e.g., perlecan, biglycan, and syndecans 1 and 3) and mitogenesis-related signaling proteins (e.g., mitogen-activated protein kinase 3, signal transducers and activators of transcription 2, 3, and 6, and early growth response factor 1). In contrast, most up-regulated genes (e.g., caspase-3, p21, tissue inhibitor of metalloproteinases 1, 2, and 3, and adenomatosis polyposis coli) are known for their antiangiogenic functions which include the promotion of cell apoptosis and cell cycle arrest and the inhibition of tumor growth and metastasis. These results show that the antiangiogenic activity of antithrombin is mediated at least in part by a global genetic reprogramming of endothelial cells and strongly implicate an endothelial cell ligand-receptor signaling mechanism in this reprogramming. (Cancer Res 2006; 66(10): 5047-55)
Rab38 Modulates Proteinuria in Model of Hypertension-Associated Renal Disease
Authors: Artur Rangel-Filho, Jozef Lazar, Carol Moreno, Aron Geurts, Howard J. Jacob
Journal: Journal of the American Society of Nephrology (2013)

We previously reported that the fawn-hooded hypertensive (FHH) rat is a natural Rab38 knockout, supported by a congenic animal (FHH.BN-Rab38) having less proteinuria than FHH animals. Because these congenic animals contain Brown Norway (BN) alleles for five other named genes; however, a causal role for Rab38 in the FHH phenotype remains uncertain. Here, we used transgenic and knockout models to validate Rab38 and to exclude other genes within the 1.5 Mb congenic region from involvement in causing the FHH phenotype. Transgenic rats homozygous for the wild-type Rab38 BN allele on the FHH background exhibited phenotypic rescue, having 43% lower proteinuria and 75% lower albuminuria than nontransgenic FHH littermates. Conversely, knockout of the Rab38 gene on the FHH.BN-Rab38 congenic line recapitulated a proteinuric phenotype indistinguishable from the FHH strain. In addition, in cultured proximal tubule LLC-PK1 cells, knockdown of Rab38 mRNA significantly decreased endocytosis of colloidal gold-coupled albumin, supporting the hypothesis that Rab38 modulates proteinuria through effects on tubular re-uptake and not by altering glomerular permeability. Taken together, these findings validate Rab38 as a gene having a causal role in determining the phenotype of the FHH rat, which models hypertension-associated renal disease. Furthermore, our data suggest that Rab38 affects urinary protein excretion via effects in the proximal tubule.
Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Français de Pneumo-Cancérologie (GFPC) Protocol 95-1
Authors: G. Robinet, P. Thomas, J.L. Breton, H. Léna, S. Gouva, G. Dabouis, J. Bennouna, P.J. Souquet, P. Balmes, L. Thiberville, P. Fournel, E. Quoix, R. Riou, P. Rebattu, M. Pérol, D. Paillotin, F. Mornex
Journal: Annals of Oncology (2001)
Collagen triple helix repeat containing-1 inhibits transforming growth factor-β1-induced collagen type I expression in keloid
Authors: J. Li, J. Cao, M. Li, Y. Yu, Y. Yang, X. Xiao, Z. Wu, L. Wang, Y. Tu, H. Chen
Journal: British Journal of Dermatology (2011)

Background Keloids are benign skin tumours occurring during wound healing in genetically predisposed patients. There is evidence that transforming growth factor (TGF)-β is involved in keloid formation. Collagen triple helix repeat containing-1 (Cthrc1) was identified as a novel gene expressed in the adventitia and neointima on arterial injury. It is indicated to be a cell type-specific inhibitor of TGF-β, which functionally increases cell migration while reducing collagen type I and III deposition. However, to our knowledge expression and regulatory mechanisms of Cthrc1 and TGF-β1 in keloid and normal skin have not been studied before. Objectives Cthrc1 gene regulation and potential role in keloid formation were determined, and its correlation with TGF-β1 involved in keloid pathogenesis was examined in human fibroblasts of keloids and normal skin. Methods The expression of Cthrc1 and TGF-β1 was investigated in fibroblasts of keloid and normal skin. Collagen type I expression and collagen synthesis in keloid fibroblasts induced by TGF-β1 were examined. Then, recombinant Cthrc1 was applied to assess its correlation with TGF-β1. Results Increased TGF-β1 and Cthrc1 expression was examined in keloid compared with normal skin. Cthrc1 expression increased in a concentration-dependent manner induced by TGF-β1 in keloid fibroblasts. TGF-β1 stimulated collagen type I expression and collagen synthesis in keloid fibroblasts, which can be reversed by recombinant Cthrc1. Conclusions TGF-β1 was upregulated in keloid fibroblasts and recombinant Cthrc1 inhibited TGF-β1-stimulated collagen type I synthesis, which suggests that Cthrc1 may be a potential therapeutic option for keloids.
The SMARCA2/4 ATPase Domain Surpasses the Bromodomain as a Drug Target in SWI/SNF-Mutant Cancers: Insights from cDNA Rescue and PFI-3 Inhibitor Studies
Authors: Bhavatarini Vangamudi, Thomas A. Paul, Parantu K. Shah, Maria Kost-Alimova, Lisa Nottebaum, Xi Shi, Yanai Zhan, Elisabetta Leo, Harshad S. Mahadeshwar, Alexei Protopopov, Andrew Futreal, Trang N. Tieu, Mike Peoples, Timothy P. Heffernan, Joseph R. Marszalek, Carlo Toniatti, Alessia Petrocchi, Dominique Verhelle, Dafydd R. Owen, Giulio Draetta, Philip Jones, Wylie S. Palmer, Shikhar Sharma, Jannik N. Andersen
Journal: Cancer Research (2015)

The SWI/SNF multisubunit complex modulates chromatin structure through the activity of two mutually exclusive catalytic subunits, SMARCA2 and SMARCA4, which both contain a bromodomain and an ATPase domain. Using RNAi, cancer-specific vulnerabilities have been identified in SWI/SNF-mutant tumors, including SMARCA4-deficient lung cancer; however, the contribution of conserved, druggable protein domains to this anticancer phenotype is unknown. Here, we functionally deconstruct the SMARCA2/4 paralog dependence of cancer cells using bioinformatics, genetic, and pharmacologic tools. We evaluate a selective SMARCA2/4 bromodomain inhibitor (PFI-3) and characterize its activity in chromatin-binding and cell-functional assays focusing on cells with altered SWI/SNF complex (e.g., lung, synovial sarcoma, leukemia, and rhabdoid tumors). We demonstrate that PFI-3 is a potent, cell-permeable probe capable of displacing ectopically expressed, GFP-tagged SMARCA2-bromodomain from chromatin, yet contrary to target knockdown, the inhibitor fails to display an antiproliferative phenotype. Mechanistically, the lack of pharmacologic efficacy is reconciled by the failure of bromodomain inhibition to displace endogenous, full-length SMARCA2 from chromatin as determined by in situ cell extraction, chromatin immunoprecipitation, and target gene expression studies. Furthermore, using inducible RNAi and cDNA complementation (bromodomain- and ATPase-dead constructs), we unequivocally identify the ATPase domain, and not the bromodomain of SMARCA2, as the relevant therapeutic target with the catalytic activity suppressing defined transcriptional programs. Taken together, our complementary genetic and pharmacologic studies exemplify a general strategy for multidomain protein drug-target validation and in case of SMARCA2/4 highlight the potential for drugging the more challenging helicase/ATPase domain to deliver on the promise of synthetic-lethality therapy.
Collaboratively charting the gene-to-phenotype network of human congenital heart defects
Authors: Roland Barriot, Jeroen Breckpot, Bernard Thienpont, Sylvain Brohée, Steven Van Vooren, Bert Coessens, Leon-Charles Tranchevent, Peter Van Loo, Marc Gewillig, Koenraad Devriendt, Yves Moreau
Journal: Genome Medicine (2010)

How to efficiently integrate the daily practice of molecular biologists, geneticists, and clinicians with the emerging computational strategies from systems biology is still much of an open question.We built on the recent advances in Wiki-based technologies to develop a collaborative knowledge base and gene prioritization portal aimed at mapping genes and genomic regions, and untangling their relations with corresponding human phenotypes, congenital heart defects (CHDs). This portal is not only an evolving community repository of current knowledge on the genetic basis of CHDs, but also a collaborative environment for the study of candidate genes potentially implicated in CHDs - in particular by integrating recent strategies for the statistical prioritization of candidate genes. It thus serves and connects the broad community that is facing CHDs, ranging from the pediatric cardiologist and clinical geneticist to the basic investigator of cardiogenesis.This study describes the first specialized portal to collaboratively annotate and analyze gene-phenotype networks. Of broad interest to the biological community, we argue that such portals will play a significant role in systems biology studies of numerous complex biological processes.CHDWiki is accessible at http://www.esat.kuleuven.be/~bioiuser/chdwiki.
NSE, a Potential Biomarker, Is Closely Connected to Diabetic Peripheral Neuropathy
Authors: Jianbo Li, Hongman Zhang, Min Xie, Lingfei Yan, Jiawei Chen, Hongxing Wang
Journal: Diabetes Care (2013)

OBJECTIVE To explore the relationship between serum neuron-specific enolase (NSE) levels and diabetic neuropathy. RESEARCH DESIGN AND METHODS Type 1 or 2 diabetic and healthy control subjects (n = 568) were randomly enrolled in a cross-sectional study. Diabetic neuropathy status was documented by the presence of clinical symptoms or signs, electromyography, quantitative sensory tests, and cardiac autonomic neuropathy tests. The severity of the neuropathy was staged by composite scores. Serum NSE was measured using electrochemiluminescence immunoassay. The demographic and clinical variables were obtained through an interviewer questionnaire. RESULTS Serum NSE levels increased slightly in diabetic subjects compared with normal subjects (9.1 [1.5] vs. 8.7 [1.7], P = 0.037), and the levels increased greatly in diabetic subjects with neuropathy compared with those without (10.8 [2.8] vs. 9.1 [1.5], P = 0.000). The association of NSE with diabetic neuropathy was independent of the hyperglycemic state (fasting blood glucose, HbA1c, duration, and the type of diabetes) and other potential confounders affecting NSE levels (e.g., age, sex, and renal status) (odds ratio 1.48 [1.13–1.74], P = 0.001). In addition, NSE levels increased with and were closely correlated to the stages of neuropathy (r = 0.63 [0.52–0.74], P = 0.000). The optimal cutoff point for serum NSE levels to distinguish patients with diabetic neuropathy from those without was 10.10 μg/L, with a sensitivity of 66.3% and a specificity of 72.5%. CONCLUSIONS Serum NSE levels are closely associated with peripheral neuropathy in patients with diabetes. Future studies are warranted to clarify the relationship.
Primary eosinophilic disorders of the gastrointestinal tract
Authors: B M Yan, E A Shaffer
Journal: Gut (2008)

Eosinophils are important effector cells of the innate immune system. Eosinophilic infiltrative disorders of the gastrointestinal tract, though recognised for decades, have recently witnessed a resurgence of interest, particularly for oesophageal disease. A more comprehensive basis for eosinophilic infiltration and activation has identified interleukin 5 (IL5) as a key cytokine for the differentiation and proliferation of eosinophils, while eotaxins promote the recruitment of mature eosinophils to the gut. When activated, eosinophils release multiple cytotoxic agents and immunomodulatory cytokines, resulting in local inflammation and tissue damage. Although eosinophils normally convey a defence against unwanted interlopers such as parasites, in the absence of such inciting agents, their accumulation and activation can elicit the primary infiltrative disorders of the gut: eosinophilic oesophagitis, gastroenteritis and colitis. Diagnosis of these disorders is dependent on the clinical presentation, endoscopic findings (particularly for eosinophilic oesophagitis), and most importantly, histological confirmation. Dietary modifications and topical corticosteroids are first-line treatments for eosinophilic oesophagitis. Systemic corticosteroids are the mainstay of treatment for eosinophilic gastroenteritis; surgery may be required depending on the layer of mucosa involved. Eosinophilic colitis most often occurs in infants; removal of the causative allergen usually results in a complete response. Steroids may be required for older children/adolescents or adults. This review summarises current knowledge on the trafficking of eosinophils to the gastrointestinal tract and the clinical management of the primary disorders of eosinophilic oesophagitis, eosinophilic gastroenteritis and eosinophilic colitis.
Challenges in pulmonary fibrosis: 7 {middle dot} Novel therapies and lung transplantation
Authors: T J Williams, J W Wilson
Journal: Thorax (2008)

The spectrum of diseases collectively known as pulmonary fibrosis does not have reliable therapeutic options. Many treatment protocols have been the subject of clinical trials, resulting in few significant improvements in outcome. Recently, cellular mechanisms have been the focus of investigations in progenitor cell studies, suggesting an immunomodulatory role for mesenchymal stem cells. The possible role of fibrogenic cytokines and the use of antagonist molecules are promising for future therapies. A range of anti-inflammatory treatments, including macrolide antibiotics, may also hold promise. When medical therapy has been unsuccessful in altering the course of the disease, lung transplantation may offer a significant survival advantage. Improvement in pre-transplant assessment and postoperative care, combined with more effective immunosuppressive regimes, has seen survival rates of 40% after 5 years. New options for therapy will lead to improved survival in coming years.
Binding of apolipoprotein A-I and acetaldehyde-modified apolipoprotein A-I to liver extracellular matrix
Authors: V Paradis, P Mathurin, V Ratziu, T Poynard, P Bedossa
Journal: Hepatology (1996)

Apolipoprotein A-I (Apo A-I), a protein produced mainly by hepatocytes, is decreased in the sera of alcoholic patients with liver fibrosis and cirrhosis. To explain this decrease, we investigated possible interactions between liver extracellular matrix (ECM) and Apo A-I. Using a solid-phase binding assay, we evaluated the binding of Apo A-I to the different liver matrix components. Apo A-I bound significantly to fibronectin (FN) (optical density [OD] = 1.11 +/- .26, P = .01) and collagen (C) I (OD = 0.91 +/- 0.22, P = .02) in comparison with bovine serum albumin (BSA) (OD = 0.26 +/- 0.16). Binding of Apo A-I to fibronectin was concentration dependent and saturable. Apo A-I bound also to ECM in vivo because Apo A-I was detected by immunofluorescence on fibrous septa in liver biopsy specimens of alcoholic patients. Because a negative correlation between Apo A-I and liver fibrosis is amplified in alcoholic patients, we investigated whether the in vitro formation of Apo A-I/acetaldehyde complex (adducts) increased the binding of Apo A-I to the ECM. We showed that the amount of Apo A-I that bound to FN was significantly higher with acetaldehyde-modified Apo A-I (OD = 2.18 +/- 0.19, P = .01) than with native Apo A-I. This increase was probably related to the formation and binding of Apo A-I dimers, because immunoblot of in vitro acetaldehyde-modified Apo A-I showed the formation of dimeric Apo A-I. In conclusion, FN binds both native and acetaldehyde-modified Apo A-I. Because FN is deposited early and in excess during liver fibrosis, a storage mechanism of Apo A-I on newly deposited fibronectin would explain, in part, the decrease observed in alcoholic patients with liver fibrosis.
Cardiac work and efficiency
Authors: N Westerhof
Journal: Cardiovascular Research (2000)

See article by Kiriazis and Gibbs [1] ( pages 111 -119)two parts, activation and basal oxygen consumption.The in this issue.first depends on excitation-contraction coupling and is proportional to cardiac contractility.For the quiescent muscle the PVA and the oxygen cost of activation both are zero.The remaining part results from all other processes 1. Work output and efficiency of the heart requiring oxygen such as ion pumps.With increased cardiac contractility the oxygen cost of activation (Fig. 1, 1.1.Pressure-volume relation and oxygen consumption bottom) is increased in a proportional manner but the slope of the relation between PVA and oxygen consumption is Many researchers have tried to relate cardiac energy not affected.metabolism in terms of oxygen consumption or heat The relation between PVA and V holds for all types of O 2 production to mechanical performance.One now popular contractions, from isovolumic to isobaric ('unloaded') and accepted mechanical parameter is based on the prescontractions.Isovolumic contractions correspond to the sure-volume relations found in the intact heart where largest PVA and thus the largest oxygen consumption [3].pressure is plotted as a function of volume over the cardiacWe see that external work is not a good measure of oxygen cycle [2].The curve that is followed during the heartbeat consumption.consists of the following four parts (Fig. 1 , top). Starting atMany other relations between oxygen consumption and end-diastole (right bottom corner) ventricular pressure mechanical or hemodynamic parameters have been proincreases while volume remains constant (isovolumic posed.The two best known are the rate pressure product contraction), during the ejection phase volume decreases (RPP) and the tension time index (TTI).but pressure changes little, and, after closure of the aorticThe RPP is the product of systolic pressure (P ) and s valves isovolumic relaxation ensues, which is followed by heart rate and is used as a measure of oxygen consumption the filling phase.The area circumscribed is external in many biochemical studies.When these studies are mechanical work per beat.The triangular area between the performed in isolated hearts in Langendorff perfusion, i.e. systolic and diastolic pressure-volume relations and no external work is performed, the PVA(0.5P(V 2 s ed 2 bounded by isovolumic relaxation is 'potential energy'.V )(0.5P /E , with V is end-diastolic volume, and V
Myocarditis-inducing epitope of myosin binds constitutively and stably to I-Ak on antigen-presenting cells in the heart.
Authors: D L Donermeyer, K W Beisel, P M Allen, S C Smith
Journal: The Journal of Experimental Medicine (1995)

Immune interactions in the heart were studied using a murine model of myosin-induced autoimmune myocarditis. A T cell hybridoma specific for mouse cardiac myosin was generated from A/J mice and used to demonstrate that endogenous myosin/I-Ak complexes are constitutively expressed on antigen-presenting cells in the heart. This T cell hybridoma, Seu.5, was used as a functional probe to identify a myocarditis-inducing epitope of cardiac myosin. Overlapping peptides based on the cardiac myosin heavy chain alpha (myhc alpha) sequences were synthesized and tested for their ability to stimulate Seu.5 T cells. One peptide, myhc alpha (325-357) strongly stimulated the Seu.5 T cells, localizing the epitope to this region of the myhc alpha molecule. Using truncated peptides, the epitope was further localized to residues 334-352. The myhc alpha (334-352) peptide strongly induced myocarditis when administered to A/J mice, which was histologically indistinguishable from that induced by myosin. The myhc alpha (334-352) epitope was present in cardiac myosin and not skeletal muscle myosins, providing a biochemical basis for the cardiac specificity of this autoimmune disease. Induction of myocarditis by this epitope was restricted to the myhc alpha isoform and not the myhc beta isoform, suggesting there may be a difference in the efficiency of generating tolerance to these isoforms of cardiac myosin, which are differentially developmentally regulated. The myhc alpha (334-352) epitope bound to purified I-Ak molecules in a similar manner to other I-Ak-restricted immunogenic epitopes, HEL(48-61) and RNase(43-56). Importantly, the myhc alpha (334-352) epitope was able to bind to I-Ak molecules on the surface of antigen-presenting cells in a stable manner. These findings demonstrate that autoantigenic epitopes can behave in a dominant manner and constitutively bind to class II molecules in the target organ in a similar manner to foreign immunogenic epitopes.
Domains of the TCR beta-chain required for early thymocyte development.
Authors: H Jacobs, J Iacomini, M van de Ven, S Tonegawa, A Berns
Journal: The Journal of Experimental Medicine (1996)

The T cell receptor beta (TCR beta) chain controls the developmental transition from CD4-CD8- to CD4+8+thymocytes. We show that the extracellular constant region and the transmembrane region, but not the variable domain or cytoplasmic tail of the TCR beta chain are required for this differentiation step. TCR beta mutant chains lacking the cytoplasmic tail can be found at the cell surface both in functional TCR/CD3 complexes and in a GPI-anchored monomeric form indicating that the cytoplasmic tail of the TCR beta chain functions as an ER retention signal. The concordance between cell surface expression of the mutant chains as TCR/CD3 complexes and their capacity to mediate thymocyte differentiation supports the CD3 mediated feedback model in which preTCR/CD3 complexes control the developmental transition from CD4-CD8- to CD4+CD8+thymocytes.