tbuckley/cabot-search huggingface dataset:
Endogenous IRBP can be dispensable for generation of natural CD4+CD25+ regulatory T cells that protect from IRBP-induced retinal autoimmunity
Authors: Rafael S. Grajewski, Phyllis B. Silver, Rajeev K. Agarwal, Shao-Bo Su, Chi-Chao Chan, Gregory I. Liou, Rachel R. Caspi
Journal: The Journal of Experimental Medicine (2006)

Susceptibility to experimental autoimmune uveitis (EAU), a model for human uveitis induced in mice with the retinal antigen interphotoreceptor retinoid-binding protein (IRBP), is controlled by “natural” CD4+CD25+ regulatory T (T reg) cells. To examine whether endogenous expression of IRBP is necessary to generate these T reg cells, we studied responses of IRBP knockout (KO) versus wild-type (WT) mice. Unexpectedly, not only WT but also IRBP KO mice immunized with a uveitogenic regimen of IRBP in complete Freund's adjuvant (CFA) exhibited CD25+ regulatory cells that could be depleted by PC61 treatment, which suppressed development of uveitogenic effector T cells and decreased immunological responses to IRBP. These EAU-relevant T reg cells were not IRBP specific, as their activity was not present in IRBP KO mice immunized with IRBP in incomplete Freund's adjuvant (IFA), lacking mycobacteria (whereas the same mice exhibited normal T reg cell activity to retinal arrestin in IFA). We propose that mycobacterial components in CFA activate T reg cells of other specificities to inhibit generation of IRBP-specific effector T cells in a bystander fashion, indicating that effective T reg cells can be antigen nonspecific. Our data also provide the first evidence that generation of specific T reg cells to a native autoantigen in a mouse with a diverse T cell repertoire requires a cognate interaction.
Abstract 656: Promoter hypermethylation and silencing of tumor suppressor genes RASSF1A, WIF1, SLIT2 and ROBO1 in triple negative breast carcinomas.
Authors: Carolina Alvarez, Gloria Garrido, Patricia Gajardo, Alonso Quiroz, Valeria Cornejo, Wanda Fernandez, Mauricio Camus, Pilar Carvallo
Journal: Cancer Research (2013)

Abstract Triple negative breast cancers represent 10-17% of all breast carcinomas. They display a high histological grade, a more aggressive clinical behavior and they lack any specific treatment, thus are associated to a bad prognosis. As other cancer types, this cancer is caused by sequential accumulation of mutations and genomic alterations involving tumor suppressor genes and oncogenes. In this matter, inactivation of tumor suppressor genes may occur by deletion, promoter hypermethylation or point mutations. In previous study by array CGH we found several tumor suppressor candidate genes deleted in a hereditary breast cancer set of tumors. In addition we studied 4 of these tumor suppressor genes RASSF1A, WIF1, SLIT2 and ROBO1 in a non triple negative set of breast cancer tumors, and found a high frequency of promoter methylation, statistically associated with loss of protein expression for RASSF1A and WIF1. In the present study we aimed to extend the analysis to triple negative breast cancer tumors due to their clinical relevance. Methylation analysis through MS-PCR revealed that RASSF1A promoter was hypermethylated in 52.9% of triple negative tumors, and presents loss of expression in 80.6% of the tumors. WIF1 promoter was hypermethylated in 89.1% and its protein expression was downregulated in 63.1% of the tumors. For SLIT2 we found frequent promoter hypermethylation among tumors (82.6%) showing loss of expression in 88% of the tumors. MS-PCR analyses were not informative for ROBO1, but protein expression was reduced in 49% of all tumors. Our results show that a high percentage of tumors present silencing of RASSF1A, WIF1, SLIT2 and/or ROBO1, and therefore implying the impairment of the pathways they represent. This findings support these genes may have an important role in triple negative breast tumor development. Fondecyt 1080595. Citation Format: Carolina Alvarez, Gloria Garrido, Patricia Gajardo, Alonso Quiroz, Valeria Cornejo, Wanda Fernandez, Mauricio Camus, Pilar Carvallo. Promoter hypermethylation and silencing of tumor suppressor genes RASSF1A, WIF1, SLIT2 and ROBO1 in triple negative breast carcinomas. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 656. doi:10.1158/1538-7445.AM2013-656
DIMERIZATION AS A REGULATORY MECHANISM IN SIGNAL TRANSDUCTION
Authors: Juli D. Klemm, Stuart L. Schreiber, Gerald R. Crabtree
Journal: Annual Review of Immunology (1998)

▪ Abstract Dynamic protein-protein interactions are a key component of biological regulatory networks. Dimerization events—physical interactions between related proteins—represent an important subset of protein-protein interactions and are frequently employed in transducing signals from the cell surface to the nucleus. Importantly, dimerization between different members of a protein family can generate considerable functional diversity when different protein combinations have distinct regulatory properties. A survey of processes known to be controlled by dimerization illustrates the diverse physical and biological outcomes achieved through this regulatory mechanism. These include: facilitated proximity and orientation; differential regulation by heterodimerization; generation of temporal and spatial boundaries; enhancement of specificity; and regulated monomer-to-dimer transitions. Elucidation of these mechanisms has led to the design of new approaches to study and to manipulate signal transduction pathways.
Interleukin-1 blockade does not prevent acute graft-versus-host disease: results of a randomized, double-blind, placebo-controlled trial of interleukin-1 receptor antagonist in allogeneic bone marrow transplantation
Authors: Joseph H. Antin, Daniel Weisdorf, Donna Neuberg, Roberta Nicklow, Shawn Clouthier, Stephanie J. Lee, Edwin Alyea, Carol McGarigle, Bruce R. Blazar, Stephen Sonis, Robert J. Soiffer, James L.M. Ferrara
Journal: Blood (2002)
Identification and Characterization of<i>Survival-Related Gene</i>, a Novel Cell Survival Gene Controlling Apoptosis and Tumorigenesis
Authors: Zeng-Rong Yuan, Ruoxiang Wang, Jennifer Solomon, Xunyi Luo, Hong Sun, Liying Zhang, Yufang Shi
Journal: Cancer Research (2005)

Abstract Apoptosis plays a critical role in cellular homeostasis during development, immune responses, and tumorigenesis. Recent studies have identified a number of genes that control this process. We report here our identification of a novel cell survival-related gene (SRG) from a human expression cDNA library by functional cloning. SRG shows no significant nucleotide sequence homology to any known genes in the Genbank. Our fluorescence in situ hybridization analysis has estimated that SRG is located at 1p36, agreeing with the location at 1p36.22 in the human genome sequence. SRG encodes a putative protein of 172 amino acids, which is mainly located in the perinuclear region. Northern blotting analysis indicates that SRG is highly expressed in many human cancer cell lines although it is low in most tissues except liver and placenta. To investigate the function of SRG in apoptosis, we transfected SRG cDNA into BAF/BO3 and B16/F0 cells and induced apoptosis by cytokine/serum deprivation. We found that SRG-transfected cells are resistant to apoptosis induced by cytokine/serum deprivation. In addition, mice bearing SRG-transfected melanoma had more tumor formation and larger tumor growth. Melanoma transfected with antisense SRG showed significantly less tumor formation and smaller tumor growth. Interestingly, mouse SRG gene was also identified on chromosome 4 and blocking SRG expression with small interfering RNA promoted serum deprivation–induced apoptosis of NIH3T3 cells. Our results show that SRG is a novel cell survival gene that critically controls apoptosis and tumor formation.
ApoE variant p.V236E is associated with markedly reduced risk of Alzheimer’s disease
Authors: Christopher W Medway, Samer Abdul-Hay, Tynickwa Mims, L i Ma, Gina Bisceglio, Fanggeng Zou, Shane Pankratz, Sigrid B Sando, Jan O Aasly, Maria Barcikowska, Joanna Siuda, Zbigniew K Wszolek, Owen A Ross, Minerva Carrasquillo, Dennis W Dickson, Neill Graff-Radford, Ronald C Petersen, Nilüfer Ertekin-Taner, Kevin Morgan, Guojun Bu, Steven G Younkin
Journal: Molecular Neurodegeneration (2014)

Recent genome-wide association studies (GWAS) of late-onset Alzheimer's disease (LOAD) have identified single nucleotide polymorphisms (SNPs) which show significant association at the well-known APOE locus and at nineteen additional loci. Among the functional, disease-associated variants at these loci, missense variants are particularly important because they can be readily investigated in model systems to search for novel therapeutic targets. It is now possible to perform a low-cost search for these "actionable" variants by genotyping the missense variants at known LOAD loci already cataloged on the Exome Variant Server (EVS). In this proof-of-principle study designed to explore the efficacy of this approach, we analyzed three rare EVS variants in APOE, p.L28P, p.R145C and p.V236E, in our case control series of 9114 subjects. p.R145C proved to be too rare to analyze effectively. The minor allele of p.L28P, which was in complete linkage disequilibrium (D' = 1) with the far more common APOE ϵ4 allele, showed no association with LOAD (P = 0.75) independent of the APOE ϵ4 allele. p.V236E was significantly associated with a marked reduction in risk of LOAD (P = 7.5×10−05; OR = 0.10, 0.03 to 0.45). The minor allele of p.V236E, which was in complete linkage disequilibrium (D' = 1) with the common APOE ϵ3 allele, identifies a novel LOAD-associated haplotype (APOE ϵ3b) which is associated with decreased risk of LOAD independent of the more abundant APOE ϵ2, ϵ3 and ϵ4 haplotypes. Follow-up studies will be important to confirm the significance of this association and to better define its odds ratio. The ApoE p.V236E substitution is the first disease-associated change located in the lipid-binding, C-terminal domain of the protein. Thus our study (i) identifies a novel APOE missense variant which may profitably be studied to better understand how ApoE function may be modified to reduce risk of LOAD and (ii) indicates that analysis of protein-altering variants cataloged on the EVS can be a cost-effective way to identify actionable functional variants at recently discovered LOAD loci.
Brains, genes, and language evolution: A new synthesis
Authors: Morten H. Christiansen, Nick Chater
Journal: Behavioral and Brain Sciences (2008)

Abstract Our target article argued that a genetically specified Universal Grammar (UG), capturing arbitrary properties of languages, is not tenable on evolutionary grounds, and that the close fit between language and language learners arises because language is shaped by the brain, rather than the reverse. Few commentaries defend a genetically specified UG. Some commentators argue that we underestimate the importance of processes of cultural transmission; some propose additional cognitive and brain mechanisms that may constrain language and perhaps differentiate humans from nonhuman primates; and others argue that we overstate or understate the case against co-evolution of language genes. In engaging with these issues, we suggest that a new synthesis concerning the relationship between brains, genes, and language may be emerging.
Primary Myeloproliferative Disorder and Hepatic Vein Thrombosis
Authors: DOMINIQUE VALLA
Journal: Annals of Internal Medicine (1985)

We assessed the prevalence of overt and latent primary myeloproliferative disorders in hepatic vein thrombosis. Cultures of bone marrow or peripheral blood mononuclear cells were done in 20 patients with Budd-Chiari syndrome. Erythroid colony formation in the absence of erythropoietin, which is a reliable indicator for a primary myeloproliferative disorder, was seen in 16 patients in whom Budd-Chiari syndrome was due to hepatic vein thrombosis, including 13 women aged 18 to 45 years. Among these 16 patients, the conventional criteria for the diagnosis of a primary myeloproliferative disorder were met in only 2. Primary myeloproliferative disorder, often without peripheral blood changes, is a major cause of hepatic vein thrombosis in young women.
Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis
Authors: J Grove, A K Daly, M F Bassendine, C P Day
Journal: Hepatology (1997)

Twin concordance studies suggest that genetic factors play a role in determining why only a minority of heavy drinkers develop hepatitis and cirrhosis. Tumor necrosis factor α (TNF-α) has emerged as the “final common pathway” in the pathogenesis of alcohol-related hepatic necro-inflammation. We have examined the frequency of the two recently described polymorphisms of the TNF-α promoter in 150 patients with biopsy-proven alcoholic liver disease and 145 healthy volunteers. There was a significant excess of the rare allele ( TNFA-A ; G( −238 ) → A) at position −238 in patients with steatohepatitis compared with controls or patients without this lesion. This is consistent with previous suggestions that the TNFA-A allele, which falls within a putative Y regulation box of the TNF-α promoter, is associated with increased TNF-α expression. No differences were observed for the polymorphism at position −308.
Taming a Mutinous Mutant: An Errant Receptor Becomes a Prime Cancer Target
Authors: B. Goldman
Journal: JNCI Journal of the National Cancer Institute (2007)

Half of the patients were still alive 30 months or more after their diagnosis. On average, patients in the vaccine trial remained tumor free for about 12 months versus about 7 months in patients on either temozolomide regimen. About two-thirds were still alive 2 years after diagnosis, versus 5% of unvaccinated patients with EGFRvIII-positive glioblastomas. While there is reason to be optimistic, the Duke – M. D. Anderson trial was tiny and not randomized so it must be evaluated cautiously. And the glioblastoma vaccine is not a cure. The cancer always recurs because glioblastomas are highly heterogeneous cancers — they comprise many clusters of cells with different features — and the vaccine-primed immune system spares those tumor cells that are devoid of EGFRvIII. Still, in each of nine recurrent tumors examined for its presence, none of the mutant protein remained, Heimberger says, suggesting the vaccine is performing as designed. But why does this one work when so many previous attempts have failed? First, these were newly diagnosed patients, in better shape than patients who have failed prior therapies, Heimberger says. Second, only residual traces of the tumor remained after surgery, disabling the myriad decoys and traps solid tumors evolve to defl ect immune responses. Finally, EGFRvIII is an ideal immuno
Serial FDG–PET/CT for early outcome prediction in patients with metastatic colorectal cancer undergoing chemotherapy
Authors: A. Hendlisz, V. Golfinopoulos, C. Garcia, A. Covas, P. Emonts, L. Ameye, M. Paesmans, A. Deleporte, G. Machiels, E. Toussaint, B. Vanderlinden, A. Awada, M. Piccart, P. Flamen
Journal: Annals of Oncology (2011)
CONTRIBUTIONS TO THE PATHOLOGY OF EXPERIMENTAL VIRUS ENCEPHALITIS
Authors: Simon Flexner
Journal: The Journal of Experimental Medicine (1928)

In this paper, three strains of the herpes virus have been dealt with. The H.F. II strain was obtained from the subject H.F. 4 years after the H.F. I strain was secured. H.F. is a victim of recurrent herpes. If the subject is also a chronic carrier of the herpes virus, then it is not one, but two or more strains which are persistently carried. The H.F. II strain is of mitigated pathogenic action for the rabbit, as compared with the H.F. I strain; it is to be classed as dermatotropic rather than neurotropic. And yet, in the subject there was no indication that the attack of herpes provoked was different from the other attacks associated with the H.F. I virus. The other two herpes strains derive their interest from the fact that they came also from persons who suffer from repeated attacks of labial herpes. One strain proved highly neurotropic, resembling in this respect the H.F. I strain; the other was hardly neurotropic at all, but was none the less definitely dermatotropic. It may be possible at a later date to secure other samples of virus from these individuals for comparison. The dermatotropic F. strain penetrates to the central nervous system far more readily and certainly from the skin than from corneal surfaces. The recovered inoculated rabbits showed only relative protection to reinoculation of the herpes virus. A notable difference appeared in the degree of protection acquired, on the one hand by the cornea and on the other by the brain. While the one was partial, the other was complete. The complete resistance of the brain was shown (a) by the complete failure of the intracerebral inoculation, and (b) by the absence of circling movements following corneal inoculation.
Role of interleukin-4 in human immunoglobulin E formation in hu-PBL-SCID mice.
Authors: H L Spiegelberg, L Beck, H P Kocher, W C Fanslow, A H Lucas
Journal: Journal of Clinical Investigation (1994)

We studied the role of IL-4 in human IgE formation in severe combined immunodeficient mice engrafted with peripheral blood mononuclear leukocytes (hu-PBL-SCID). PBL from four nonatopic donors produced only small (< 20 ng/ml) or undetectable amounts of IgE in SCID mice whereas engrafted PBL from seven atopic donors secreted IgE with IgE serum levels reaching a mean +/- SE of 184 +/- 37 ng/ml (n = 20). Serum IgE levels peaked 2-3 wk after PBL transfer and declined thereafter with a half-life of 1-2 wk. In contrast, IgG of all subclasses reached maximum serum levels 5-7 wk after PBL transfer and declined little thereafter. Injection of a neutralizing monoclonal antibody to the human IL-4 receptor (IL-4R) on day 0 inhibited completely the IgE formation and caused an approximate twofold reduction of IgG production of all subclasses. The anti-IL-4 R antibody had no effect on IgE secretion when administered 4 wk after PBL engraftment. Incubation of PBL with IL-4 before engraftment resulted in a 10-fold increase in IgE production and could be further enhanced by 100 fold if, in addition to preincubation with IL-4, IL-4 was injected daily for 5 d after PBL transfer. This treatment with IL-4 also induced two- to threefold increase in IgG levels. IFN-gamma had no effect on either IgE or IgG subclass production. In approximately 50% of the mice, one or more IgG subclasses increased disproportionally 5 wk after PBL injection as a result of monoclonal IgG formation. These data demonstrate that PBL from atopic donors secrete IgE in SCID mice in an IL-4-dependent manner, and that IgE production can be enhanced 10- to 100-fold with exogenous human IL-4 in these mice. This mouse model is amenable for the in vivo study of immunomodulators on human IgE formation.
Serum Levels of Adipokine Retinol-Binding Protein-4 in Relation to Renal Function
Authors: Vasileios Papavasileiou, Vasilios Liakopoulos, Georgios K. Sakkas, Georgios M. Hadjigeorgiou, Georgios Koukoulis, Ioannis Stefanidis
Journal: Diabetes Care (2008)

In their recent study, Ziegelmeier et al. (1) showed that remnant kidney function and C-reactive protein are independently associated with elevated serum levels of retinol-binding protein (sRBP)-4 in hemodialysis patients. Markers of kidney function were levels of serum creatinine and glomerular filtration rate estimated by the Cockroft-Gault formula . However, since creatinine can be removed both by dialysis and remnant kidneyfunction, levels of serum creatinine and glomerular filtration rate estimated by the Cockroft-Gault formula do not exactly reflect renal function in …
Genome analysis and genome-wide proteomics of Thermococcus gammatolerans, the most radioresistant organism known amongst the Archaea
Authors: Yvan Zivanovic, Jean Armengaud, Arnaud Lagorce, Christophe Leplat, Philippe Guérin, Murielle Dutertre, Véronique Anthouard, Patrick Forterre, Patrick Wincker, Fabrice Confalonieri
Journal: Genome biology (2009)

Abstract Background Thermococcus gammatolerans was isolated from samples collected from hydrothermal chimneys. It is one of the most radioresistant organisms known amongst the Archaea. We report the determination and annotation of its complete genome sequence, its comparison with other Thermococcales genomes, and a proteomic analysis. Results T. gammatolerans has a circular chromosome of 2.045 Mbp without any extra-chromosomal elements, coding for 2,157 proteins. A thorough comparative genomics analysis revealed important but unsuspected genome plasticity differences between sequenced Thermococcus and Pyrococcus species that could not be attributed to the presence of specific mobile elements. Two virus-related regions, tgv1 and tgv2, are the only mobile elements identified in this genome. A proteogenome analysis was performed by a shotgun liquid chromatography-tandem mass spectrometry approach, allowing the identification of 10,931 unique peptides corresponding to 951 proteins. This information concurrently validates the accuracy of the genome annotation. Semi-quantification of proteins by spectral count was done on exponential- and stationary-phase cells. Insights into general catabolism, hydrogenase complexes, detoxification systems, and the DNA repair toolbox of this archaeon are revealed through this genome and proteome analysis. Conclusions This work is the first archaeal proteome investigation done at the stage of primary genome annotation. This archaeon is shown to use a large variety of metabolic pathways even under a rich medium growth condition. This proteogenomic study also indicates that the high radiotolerance of T. gammatolerans is probably due to proteins that remain to be characterized rather than a larger arsenal of known DNA repair enzymes.
FLUOCINOLONE ACETONIDE 0.2% CREAM—A CO-OPERATIVE CLINICAL TRIAL*
Authors: C. W. MARSDEN
Journal: British Journal of Dermatology (1968)

SUMMARY. The response to a 0·2% fluocinolone acetonide cream is reported in 192 patients with a variety of skin conditions. Results were particularly successful in chronic discoid lupus erythematosus, necrobiosis lipoidica, lichen planus and granuloma annulare. Some cases of pustular psoriasis of the palms and of keloids responded well. Occasional benefit occurred in mycosis fungoides and in pemphigus erythematosus but in general the results in these last 2 conditions were disappointing. No serious adverse effects were seen in this series.
Acute Pericarditis Secondary to Hydatid Cyst Rupture
Authors: Alberto Cecconi, Luis Maroto, Isidre Vilacosta, Maria Luaces, Luis Ortega, Natalia Escribano, David Vivas, Joaquín Ferreirós, Lorena Montes, Jean Paul Vilchez, Elena Fortuny, Carmen Olmos, Jose Enrique Rodriguez, Carlos Macaya
Journal: Circulation (2013)