tbuckley/cabot-search huggingface dataset:
OP0176 Clusters of Single Nucleotide Polymorphisms Within the HLA-DRB1 Gene in Relation to Antibodies Against Citrullinated Peptides in Individuals Prior to the Development of Rheumatoid Arthritis
Authors: S. Rantapää Dahlqvist, L. Ärlestig, M. Brink, J. Rönnelid, L. Klareskog
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Multiplex analysis has demonstrated the presence of several antibodies against cyclic citrullinated peptides (ACPA) preceding the development of rheumatoid arthritis (RA) by several years. Certain HLA-DRB1* alleles are strongly associated with RA. <h3>Objectives</h3> To relate the presence of different ACPA, in individuals before the onset of symptoms of RA, to single nucleotide polymorphisms (SNPs) within the HLA-DRB1 region in order to identify the SNPs most highly associated with the ACPAs analysed in the disease development. <h3>Methods</h3> The study group comprised 406 individuals, with 717 samples, who were identified before the onset of symptoms (median (IQR) 7.4 (9.3) years), of 976 population controls, who were identified as donors to the Medical Biobank of Northern Sweden. Analysis of antibodies against 10 different citrullinated peptides in plasma using a microarray system developed in collaboration with Phadia AB/Thermofisher, Uppsala, based on their ISAC platform. The highest frequencies of antibodies were found for fibrinogen (Fib) ß36-52, CEP-1, and filaggrin. Samples from the same individuals (n=370) were genotyped with the Immunochip custom array according to Illumina protocols (SNP&amp;SEQ Technology Platform, Uppsala, Sweden). 81 SNPs covering the HLA-DRB1* to DQA1* region were analysed. The Haploview software version 4.2 was used for haplotype and association analysis with a permutation test and cluster analysis (Bray-Curtis) was performed using Past software. <h3>Results</h3> Thirty-seven of the SNPs were associated with the pre-diseased individuals compared with controls. After permutation test 22 of them and six haplotypes (7-16 SNPs) remained significantly associated. Anti-CEP-1 antibodies were associated with 15 SNPs although none remained significant after permutation tests. Anti-filaggrin antibodies were related to 4 SNPs, two of which were similar as for anti-CEP-1 (rs9271588 and rs9272363), none remained significant after permutation test. Anti-Fibß36-52 antibodies were associated with 4 different SNPs compared with the other antibodies and none was significant after permutation test. Antibodies against Fibß36-52 associated with the SNPs were all within the same cluster of SNPs, whilst associations of antibodies against CEP-1 were within three different sub-clusters. One cluster of SNPs was similar to where associations to anti- filaggrin were found. <h3>Conclusions</h3> The presence of ACPA is related to a number of SNPs within the HLA- region albeit with somewhat different patterns between the various antibodies and clusters of SNPs. <h3>Disclosure of Interest</h3> None Declared
Nanotechnology-Related Environment, Health, and Safety Research
Authors: Giovanni Brandi, Elisabetta Nobili, Stefania Di Girolamo, Gianluca Grazi, Michelangelo Fiorentino, Rita Golfieri, Guido Biasco
Journal: Environmental Health Perspectives (2009)

Agency) ToxRefDB and ToxCast research programs, including the review of much of the data entered into ToxRefDB.However, Janus's comments do not address the ToxRefDB applications presented in our article, but instead create hypothetical uses of the database and reported data.For example, in Table 3 of our article (Martin et al. 2009a), we presented multigender, multi site, and multispecies rodent tumorigens in order to provide data in a systematic and computable format for predictive toxicity models incorporating potency values.In contrast, Janus and CropLife America refer to a hypothetical regulatory application of this same animal tumorigenicity data in a ranking system never suggested in our article.The U.S. EPA has gone to great lengths to make ToxRefDB and its development as transparent as possible.Three manuscripts and data sets have been published to date (Knudsen et al. 2009; Martin et al. 2009a Martin et al. , 2009b)), and the standardized vocabulary and a version of the database are available on the ToxRefDB website (U.S. EPA 2008b).We will continue to make every effort to publicly release information from ToxRefDB as it continues to develop.We recognize the complexity of pathologic progression to cancer.The end point progression scheme we presented (Martin et al. 2009a) included aggregation of prolifera tive, pre neoplastic, and neo plastic lesions for the development of predictive signatures from in vitro data coming from the ToxCast research program (U.S. EPA 2008a).This approach is not controversial in the context of predictive toxicology research and is supported by the literature (Cohen and Arnold 2008;Hanahan and Weinberg 2000).We agree that it is important to incorporate pharmacokinetics and metabolism, including chemical detoxification and activation, into predictive toxicology efforts.However, this issue is outside the scope of our article (Martin et al. 2009a) and is being addressed in other aspects of the ToxCast research program.Two additional papers on multi generational reproductive and prenatal developmental toxicity studies in ToxRefDB have been recently published (Knudsen et al. 2009; Martin et al. 2009b), again with the primary goal of providing diverse end points for predictive modeling as part of the ToxCast research program (Dix et al. 2007).Of toxicity end points in ToxRefDB, we are using only those of sufficient quality for predictive modeling, and we are taking care to distinguish between missing versus negative data.We view ToxRefDB as a valuable resource to the scientific community and one in which the U.S. EPA, stakeholders, and other interested parties can work together to ensure the success of ToxRefDB and the larger ToxCast effort.
Iminoglycinuria and hyperglycinuria are discrete human phenotypes resulting from complex mutations in proline and glycine transporters
Authors: Stefan Bröer, Charles G. Bailey, Sonja Kowalczuk, Cynthia Ng, Jessica M. Vanslambrouck, Helen Rodgers, Christiane Auray-Blais, Juleen A. Cavanaugh, Angelika Bröer, John E.J. Rasko
Journal: Journal of Clinical Investigation (2008)

Iminoglycinuria (IG) is an autosomal recessive abnormality of renal transport of glycine and the imino acids proline and hydroxyproline, but the specific genetic defect(s) have not been determined. Similarly, although the related disorder hyperglycinuria (HG) without iminoaciduria has been attributed to heterozygosity of a putative defective glycine, proline, and hydroxyproline transporter, confirming the underlying genetic defect(s) has been difficult. Here we applied a candidate gene sequencing approach in 7 families first identified through newborn IG screening programs. Both inheritance and functional studies identified the gene encoding the proton amino acid transporter SLC36A2 (PAT2) as the major gene responsible for IG in these families, and its inheritance was consistent with a classical semidominant pattern in which 2 inherited nonfunctional alleles conferred the IG phenotype, while 1 nonfunctional allele was sufficient to confer the HG phenotype. Mutations in SLC36A2 that retained residual transport activity resulted in the IG phenotype when combined with mutations in the gene encoding the imino acid transporter SLC6A20 (IMINO). Additional mutations were identified in the genes encoding the putative glycine transporter SLC6A18 (XT2) and the neutral amino acid transporter SLC6A19 (B0AT1) in families with either IG or HG, suggesting that mutations in the genes encoding these transporters may also contribute to these phenotypes. In summary, although recognized as apparently simple Mendelian disorders, IG and HG exhibit complex molecular explanations depending on a major gene and accompanying modifier genes.
Significance of Homologous Donor Blood to the Toxic Reaction in Dogs Undergoing Extracorporeal Hemodialysis
Authors: FRANK T. MAHER, LEE C. WATKINS, JAMES C. BROADBENT, JESSE L. BOLLMAN
Journal: Circulation Research (1958)

Application of hemodialysis to dogs has been complicated by an acute reaction consisting of hypotension, bradycardia and respiratory depression followed by instability and a mortality rate of about 30 per cent. This reaction appears to be a response to homologous blood used to fill the dialyzers. Sensitization occurs in survivors, and accentuated reactions with marked hemolysis are noted on subsequent challenge. Cross matching the donor and recipient bloods has not permitted an adequate determination of compatibility under the conditions of hemodialysis. Satisfactory hemodialysis may be accomplished in dogs by using autogenous blood or blood substitutes to fill the dialyzers.
EDUCATION OF THE PUBLIC IN HEALTH
Authors: William Brady
Journal: JAMA (1927)

<h3>To the Editor:</h3> —May I offer a different point of view of the subject of the education of the public in medicine and in health, discussed respectively inThe Journal, June 11, and in<i>Hygeia</i>for July? Both editorials referred to the "peculiar notion" of one newspaper health columnist as to what constitutes good exercise. As I acknowledge the "somersaulting mania" I beg to correct the editorial misunderstanding about that. I have never so intimated, nor even admitted, but have often insisted in my column that somersaulting is<i>not</i>exercise. Both articles commented on the "strange notion that disease is entirely a matter of the infecting organism and the individual's natural resistance to disease and that factors which may lessen his natural immunity have little or nothing to do with the case." I acknowledge paternity of this strange notion, too. But I submit that the editorial states the thought clumsily.
In-Stent Neointimal Proliferation Correlates With the Amount of Residual Plaque Burden Outside the Stent
Authors: Francesco Prati, Carlo Di Mario, Issam Moussa, Bernhard Reimers, Maria Teresa Mallus, Antonio Parma, Ernesto Lioy, Antonio Colombo
Journal: Circulation (1999)

Background —The aim of this study was to evaluate the relationship between residual plaque burden after coronary stent implantation and the development of late in-stent neointimal proliferation. Methods and Results —Between January 1996 and May 1997, 50 patients underwent intravascular ultrasound (IVUS) interrogation at 6±1.2 months after coronary stent implantation in native coronary arteries. IVUS images were acquired with a motorized pullback, and cross-sectional measurements were performed within the stents at 1-mm intervals. The following measurements were obtained: (1) lumen area (LA), (2) stent area (SA), (3) area delimited by the external elastic membrane (EEMA), (4) percent neointimal area calculated as (SA−LA/SA)×100, and (5) percent residual plaque area calculated as (EEMA−SA)/EEMA×100. Volume measurements within the stented segments were calculated by applying Simpson’s rule. In the pooled data analysis of 876 cross sections, linear regression showed a significant positive correlation between percent residual plaque area and percent neointimal area ( r =0.50, y = 45.03+0.29 x , P &lt;0.01). There was significant incremental increase in mean percent neointimal area for stepwise increase in percent residual plaque area. Mean percent neointimal area was 16.3±10.3% for lesions with a percent residual plaque area of &lt;50% and 27.7±11% for lesions with a percent residual plaque area of ≥50% ( P &lt;0.001). The volumetric analysis showed that the percent residual plaque volume was significantly greater in restenotic lesions compared with nonrestenotic lesions (58.7±4.3% versus 51.4±5.7%, respectively; P &lt;0.01). Conclusions —Late in-stent neointimal proliferation has a direct correlation with the amount of residual plaque burden after coronary stent implantation, supporting the hypothesis that plaque removal before stent implantation may reduce restenosis.
PWE-138 Treatment Of Patients with Chronic Hepatitis C Genotype 1 and Advanced Fibrosis with Protease Inhibitors- Il28B Discordance Results in Early Viral Decline but Late Relapse: Abstract PWE-138 Table
Authors: S Tanwar, P M Trembling, B J Hogan, J Catt, S Glasgow, N Glover, M Ju, M Hains, M T Moore, C Velazquez, T Conibear, W Labbett, D Irish, M Macartney, T Haque, E Nastouli, B Smith, P Smith, D Suri, J A Oben, M G Jacobs, G M Dusheiko, W M Rosenberg
Journal: Gut (2013)

<h3>Introduction</h3> We report the impact of host and viral factors on treatment outcome in the first 53 patients who have completed therapy for CHC with either telaprevir or boceprevir, in combination with pegylated-interferon and ribavirin (PEG/R) at our centre. <h3>Methods</h3> Patients were treatment naïve or experienced with F3 or F4 fibrosis, CHC genotype1 and HCV RNA &gt; 10,000 IU/ml. Data were collected on host and viral factors including single nucleotide polymorphisms (SNPs) in the IL28B gene noncoding region at sites rs12979860 and rs8099917. <h3>Results</h3> 53 patients (42 Caucasian, 32 F4) were treated with TVR (n = 41) and BOC (n = 12). Seven patients were treatment naïve. Subtyping was unattainable in 2 patients. Thus far, 18 patients (34%) have failed treatment and the remainder are being evaluated for SVR (24 patients with SVR-4 to date). HCV viral negativity at triple therapy week 4 was associated with treatment success in patients with rs12979860CC and rs8099917TT and rs12979860non-CC and rs8099917non-TT (OR 20.2 P-value &lt; 0.001) but not in patients with discordance between the two IL28B polymorphisms (rs12979860non-CC and rs8099917TT, P-value = NS). Despite 86% HCV RNA negativity at triple therapy week 4, patients with discordant IL28B genotype results demonstrated a failure rate of 43% predominantly due to virologic breakthrough during PEG/R. In addition, all patients who ultimately failed therapy after attaining eRVR and qualifying for shortened therapy had IL28B genotype discordance. Multivariate logistic regression identified that HCV negativity at triple therapy week 4 (p-value &lt; 0.001), rs12979860 (p-value = 0.02) and rs8099917 (p-value = 0.001) were all independent predictors of treatment outcome after accounting for the remaining factors as potential confounders. <h3>Conclusion</h3> In our prospective cohort of CHC patients with advanced fibrosis treated with PIs, HCV RNA negativity at triple therapy week 4 and both IL28B genotypes were independent predictors of treatment outcome. Despite similar rates of early viral suppression, our preliminary data indicate more favourable end of treatment results for rs12979860CC and rs8099917TT versus rs12979860non-CC and rs8099917TT. <h3>Disclosure of Interest</h3> None Declared.
Expression of Matrix Metalloproteinases, Cytokines, and Connexins in Diabetic and Nondiabetic Human Keratinocytes Before and After Transplantation Into an Ex Vivo Wound-Healing Model
Authors: Johanna M. Brandner, Steffi Zacheja, Pia Houdek, Ingrid Moll, Ralf Lobmann
Journal: Diabetes Care (2007)

OBJECTIVE—Wound healing is known to require a well-organized balance of numerous factors, e.g., cytokines, matrix metalloproteinases (MMPs), and their inhibitors, as well as direct cell-cell communication (connexins). Disruption of this balance may lead to the formation of chronic wounds such as diabetic foot ulcers. The transplantation of autologous keratinocytes is a promising therapy for diabetic foot ulcers; however, little is known about their characteristics on a molecular level. Therefore, we intended to characterize transplanted keratinocytes from diabetic and nondiabetic origin before and after transplantation. RESEARCH DESIGN AND METHODS—We isolated human keratinocytes from diabetic and nondiabetic origins and transplanted them into an ex vivo wound healing model. To characterize the keratinocytes, we investigated mRNA expression of MMP-1, MMP-2, and MMP-9; tissue inhibitor of MMP (TIMP)-1 and TIMP-2; interleukin (IL)-1β, tumor necrosis factor (TNF)-α; Cx26 (connexin 26) and Cx43; and, for connexins, immunolocalization. RESULTS—We found no significantly increased expression of the molecules investigated in cultured keratinocytes from diabetic compared with nondiabetic origin, even though there were significant differences for MMP-2, IL-1β, and TNF-α in skin biopsies. Expression of IL-1β was significantly lower in keratinocytes from diabetic origin. In the course of wound healing, differences in the dynamics of expression of MMP-1, IL-1β, and Cx43 were observed. CONCLUSIONS—Our results suggest that keratinocytes from diabetic origin are as capable for transplantation into chronic wounds as keratinocytes from healthy origin at the starting point of therapy. However, differences in expression dynamics later on might reflect the systemic influence of diabetes resulting in a memory of the transplanted keratinocytes.
Tumors of Infancy and Childhood
Authors: Nancy E. Warner
Journal: JAMA (1964)

Although the incidence of malignant tumors in children is rising, and tumors rank second only to trauma as a cause of death in childhood, yet the subject of pediatric oncology has been relatively neglected. This excellent text is an outgrowth of the seminar on childhood tumors presented by Dr. Michael in 1957 for the California Cancer Commission. In writing the book, the author has drawn upon his own extensive experience as a pediatric pathologist, as well as case material in the files of the Tumor Tissue Registry of California, and the widely scattered papers, monographs, and other sources in the literature. Following an introductory chapter on the incidence and types of childhood cancer, the tumors are discussed by systems and organs, beginning with head and neck, eye, nervous system, and bone. Next are chapters on pseudotumors of lipid metabolism and neoplasms of soft tissues, thorax, abdomen, genitourinary tract, and reproductive
Abstract 3571: Exploratory biomarker discovery for clinical development of ARQ 087, a potent pan-FGFR kinase inhibitor
Authors: Yi Yu, Xiubin Gu, Enkelada Nakuci, Xiaolan Zhao, Edward Chang, Jeff Szwaya, Jenn Castro, Laura Cousens, Cathy Bull, Yunxia Wang, Ron Savage, Carol Waghorne, Chang-Rung Chen, Dennis S. France, Edwin Clark, Thomas C.K. Chan
Journal: Cancer Research (2011)

Abstract Fibroblast growth factor receptor (FGFR) tyrosine kinase family members have gained increasing attention as potential therapeutic targets. Gene amplification, or gain-of-function translocations and mutations of these receptors, have been implicated in a variety of cancers including breast, gastric, bladder, ovarian, endometrial, lymphoma and myeloma. We have previously described the biological profiling of ARQ 087, a potent small-molecule pan-FGFR kinase inhibitor that shows anti-tumor activity in FGFR dysregulated tumor cells in vitro and in vivo. A number of cell lines with genetically-altered FGF receptors were identified that were sensitive in anti-proliferative assays to ARQ 087, including FGFR2 amplified gastric carcinoma lines KATO III and SNU-16, and endometrial lines AN3CA, MFE-296 and MFE-280 harboring FGFR2 mutants, as well as a breast cancer cell line with increased FGFR1 gene copy (MDA MB-157). Western blot pharmacodynamic analysis demonstrates that ARQ 087 inhibits FGFR phosphorylation and downstream pathway markers in these cell lines in a concentration-dependent manner. Using antibody arrays specific for known cytokines as well as regulatory proteins involved in angiogenesis and apoptosis, we have identified a number of protein biomarkers in cell lysates and in conditioned media of sensitive cell lines that changed in response to ARQ 087 exposure. Three proteins (cytochrome c, clusterin, and HTRA2) decreased in SNU-16 (ARQ 087-sensitive, FGFR amplified) but not DLD1 (ARQ 087-resistant, non FGFR expressing) cells. VEGF decreased and IL-1rα increased in SNU-16 but not in DLD1 conditioned media in response to ARQ 087. Furthermore, analysis of mouse plasma from animals bearing AN3CA tumors treated with ARQ 087 revealed a decrease in human VEGF, CXCL16, MMP-9, Serpin E1 and MIF and an increase in RANTES, IL-1β, IP-10, SDF-1, IL-1rα. TNFα, GM-CSF, IL-2, sTREM-1, sICAM-1, MIP-1β, IL-8. In summary, we have identified a number of cell lines from a broad cell line screening campaign that exhibited dysregulated FGFR pathway function and are sensitive to the anti-proliferative effects of ARQ 087. These cell lines, in turn, have been used as models in which to identify candidate biomarkers that may greatly facilitate subsequent clinical evaluation of this molecularly targeted anti-tumor agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3571. doi:10.1158/1538-7445.AM2011-3571
The Genetics of Psoriasis
Authors: Eugene M. Farber
Journal: JAMA (1972)

Psoriasis has been the subject of intense investigation in many parts of the world, but the cause of this skin disease still remains an enigma. Among studies on psoriasis, a comprehensive data gathering endeavor has provided a valuable resource for the study of the genetics of psoriasis. In the search for the etiology of any disease, a good beginning is to establish whether there is an hereditary involvement. A genetic component has long been suspected for psoriasis. Our studies on genetic and environmental factors support the hypothesis that psoriasis is compatible with multifactorial inheritance. Multifactorial inheritance is a condition in which the heritable components are alleles at an unspecified number of loci, each contributing a small effect, along with environmental factors to the phenotype. We are aware of the methodological pitfalls of the investigative approaches.<sup>1</sup>For example, the application of the twin method in the genetics of psoriasis illustrates
Utilization of Cholangiogram during Exploration for Biliary Atresia
Authors: Orvar Swenson, John H. Fisher
Journal: New England Journal of Medicine (1952)

THE results of surgical exploration of infants with biliary atresia have been discouraging, for only a small percentage of these patients have proved to have a mechanical block that could be relieved surgically. This experience prompted an evaluation of the surgeon's approach to the problem.Cases of obstructive jaundice appearing in the neonatal period, which persisted with increasing intensity beyond five weeks, were diagnosed as congenital atresia of the bile ducts. Although the jaundice might be imperceptible during the first few days of life, in four or five weeks the syndrome of obstructive jaundice developed with deep icterus, mahogany-colored urine . . .