tbuckley/cabot-search huggingface dataset:
Evidence for association of OCTN genes and IBD5 with ulcerative colitis
Authors: S Waller
Journal: Gut (2005)

Genetic association between Crohn's disease (CD) and OCTN1 (SLC22A4) C1672T/OCTN2 (SLC22A5) G-207C variants in IBD5 has recently been reported. These genes encode solute carriers and the association was suggested to be distinct from the background IBD5 risk haplotype. There have been conflicting reports of the association between markers in the IBD5 region and ulcerative colitis (UC) and interaction (epistasis) between this locus and CARD15. Our aim was to ascertain the contribution of OCTN variants to UC and CD in a large independent UK dataset, to seek genetic evidence that the OCTN association is distinct from the IBD5 risk haplotype and to identify interactions between the IBD5 and CARD15 loci.A total of 1104 unrelated Caucasian subjects with inflammatory bowel disease (IBD) (496 CD, 512 UC, 96 indeterminate) and 750 ethnically matched controls were genotyped for three single nucleotide polymorphisms (SNPs) in the CD associated genes (OCTN1+1672, OCTN2-207, and IGR2230), and two flanking IBD5 tagging SNPs, IGR2096 and IGR3096. Data were analysed by logistic regression methods within STATA.OCTN variants were as strongly associated with UC and IBD overall as they were with CD (p = 0.0001; OR 1.3 (95% confidence interval 1.1-1.5)). OCTN variants were in tight linkage disequilibrium with the extended IBD5 risk haplotype D' 0.79 and 0.88, and r2 = 0.62 and 0.72 for IGR2096 and 3096, respectively. There was no deviation from a multiplicative model of interaction between CARD15 and IBD5 on the penetrance scale.The OCTN variants were associated with susceptibility to IBD overall. The effect was equally strong in UC and CD. Although OCTN variants may account for the increased risk of IBD associated with IBD5, a role for other candidate genes within this extended haplotype was not excluded. There was no statistical evidence of interaction between CARD15 and either OCTN or IBD5 variants in susceptibility to IBD.
Heterogeneity of Angiogenic Activity in a Human Liposarcoma: a Proposed Mechanism for "No Take" of Human Tumors in Mice
Authors: E.-G. Achilles, A. Fernandez, E. N. Allred, O. Kisker, T. Udagawa, W.-D. Beecken, E. Flynn, J. Folkman
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: Tumor cells are known to be heterogeneous with respect to their metastatic activity, proliferation rate, and activity of several enzymes. However, little is known about the heterogeneity of tumor angiogenic activity. We investigated whether heterogeneity of angiogenic activity could be responsible for the well-known observation of "no take" of human tumors transplanted into immunodeficient mice. Methods: Severe combined immunodeficient (SCID) mice were xenotransplanted subcutaneously with tumor tissue (n = 55) or cell suspension of a human liposarcoma cell line (SW-872) or subclones (n = 28), with varying cell proliferation rates. Xenograft tumor growth was recorded for up to 6 months. Tumor tissues were then removed and analyzed for tumor cell apoptosis, microvessel density, and cell proliferation. All statistical tests were two-sided. Results: Pieces of tumor derived from the parental cell line or its clones gave rise to three kinds of tumors: 1) highly angiogenic and fast-growing (aggressive) tumors, 2) weakly angiogenic and slow-growing tumors, and 3) nonangiogenic and stable tumors. Most tumors retained the original phenotype of their parental tumor. Tumor volume correlated positively with microvessel density (Spearman correlation coefficient [r] = .89; P≤.0001) and inversely with tumor cell apoptosis (Spearman r = −.68; P = .002). Tumor volume was less strongly but still positively correlated with tumor cell proliferation in vivo (Spearman r = .55; P = .02). Conclusions: Human liposarcoma cells appear to be heterogeneous in their angiogenic activity. When tumor cells with little or no angiogenic activity are transplanted into SCID mice, a microscopic, dormant tumor results that may not grow further. Because such tiny tumors are neither grossly visible nor palpable, they have previously been called "no take." The finding that an angiogenic tumor can contain subpopulations of tumor cells with little or no angiogenic activity may provide a novel mechanism for dormant micrometastases, late recurrence, and changes in rate of tumor progression.
Developing Standards for Breakthrough Therapy Designation in Oncology
Authors: Sandra J. Horning, Daniel A. Haber, Wendy K.D. Selig, S. Percy Ivy, Samantha A. Roberts, Jeff D. Allen, Ellen V. Sigal, Charles L. Sawyers
Journal: Clinical Cancer Research (2013)

Abstract In July 2012, Congress passed the Food and Drug Administration Safety and Innovation Act (FDASIA). The Advancing Breakthrough Therapies for Patients Act was incorporated into a Title of FDASIA to expedite clinical development of new, potential “breakthrough” drugs or treatments that show dramatic responses in early-phase studies. Using this regulatory pathway, once a promising new drug candidate is designated as a “Breakthrough Therapy”, the U.S. Food and Drug Administration (FDA) and sponsor would collaborate to determine the best path forward to abbreviate the traditional three-phase approach to drug development. The breakthrough legislation requires that an FDA guidance be drafted that details specific requirements of the bill to aid FDA in implementing requirements of the Act. In this article, we have proposed criteria to define a product as a Breakthrough Therapy, and discussed critical components of the development process that would require flexibility in order to enable expedited development of a Breakthrough Therapy. Clin Cancer Res; 19(16); 4297–304. ©2013 AACR.
Role of Tumor Endothelium in CD4+CD25+ Regulatory T Cell Infiltration of Human Pancreatic Carcinoma
Authors: Daniel Nummer, Elisabeth Suri-Payer, Hubertus Schmitz-Winnenthal, Andreas Bonertz, Luis Galindo, Dalibor Antolovich, Moritz Koch, Markus Büchler, Jürgen Weitz, Volker Schirrmacher, Philipp Beckhove
Journal: JNCI Journal of the National Cancer Institute (2007)

Regulatory T (Treg) cells have been detected in human carcinomas and may play a role in preventing the rejection of malignant cells.We quantified Treg cells and the expression of the addressins and the respective ligands that attract them in blood and in human pancreatic tumors and adjacent nonmalignant tissues from 47 patients. The capacity of Treg cells to adhere to and transmigrate through autologous endothelial cells was tested in vitro using spheroid adhesion assays and in vivo using a xenotransplant NOD/SCID model and in the presence and absence of antibodies to addressins. All statistical tests were two-sided.More Treg cells infiltrated pancreatic carcinomas than adjacent nonmalignant pancreatic tissues (120 cells per mm2 versus 80 cells per mm2, difference = 40 cells per mm2, 95% confidence interval [CI] = 21.2 cells per mm2 to 52.1 cells per mm2; P<.001). In contrast to conventional CD4+ T cells, more blood-derived Treg cells adhered to (1.0% versus 5.2%, difference = 4.2%, 95% CI = 2.7% to 5.6%; P<.001) and transmigrated through (3332 cells versus 4976 cells, difference = 1644 cells, 95% CI = 708 cells to 2580 cells; P = .008) autologous tumor-derived endothelial cells in vitro and in vivo (458 cells versus 605 cells, difference = 147 cells, 95% CI = 50.8 to 237.2 cells; P = .04). Tumor-derived endothelial cells expressed higher levels of addressins--including mucosal adressin cell adhesion molecule-1 (MAdCAM-1), vascular cell adhesion molecule-1 (VCAM-1), CD62-E, and CD166--than endothelial cells from normal tissue. Experiments using antibodies to addressins showed that transmigration was mediated by interactions of addressins, including MAdCAM-1, VCAM-1, CD62-E, and CD166 with their respective ligands, beta7 integrin, CD62L, and CD166, which were expressed specifically on Treg cells.Tumor-induced expression of addressins on the surface of endothelial cells allows a selective transmigration of Treg cells from peripheral blood to tumor tissues.
Percutaneous Transluminal Pulmonary Angioplasty for Chronic Thromboembolic Pulmonary Hypertension with Severe Right Heart Failure
Authors: Takumi Inami, Masaharu Kataoka, Haruhisa Ishiguro, Ryoji Yanagisawa, Nobuhiko Shimura, Hideaki Yoshino, Toru Satoh
Journal: American Journal of Respiratory and Critical Care Medicine (2014)
Use of gelofusine for endoscopic mucosal resection
Authors: J. Turner, J. Green, S. Dolwani
Journal: Gut (2010)

We read with interest the recent clinical case by Sarkar et al 1 and subsequent letter by Ignjatovic and Saunders,2 where the use of gelofusine and the endoscopic mucosal resection (EMR) technique were discussed.

Gelofusine is a succinylated gelatin most commonly employed in fluid resuscitation, with a lower osmolality than 0.9% saline. Since 2004, we have routinely used an ‘EMR mix’ comprising 43 ml gelofusine, 5 ml 0.8% indigo carmine dye and 2 ml of 1:10 000 adrenaline, for the resection of flat and sessile lesions at our institution. Variable quantities of this mix are injected into the submucosal space using a 25 gauge needle, to cause sufficient lift of the lesion for resection (figure 1). Whilst …
Proteasome-Mediated Reduction in Proapoptotic Molecule Bim Renders CD4 <sup>+</sup> CD28 <sup>null</sup> T Cells Resistant to Apoptosis in Acute Coronary Syndrome
Authors: Edit Kovalcsik, Ricardo F. Antunes, Paramita Baruah, Juan Carlos Kaski, Ingrid E. Dumitriu
Journal: Circulation (2014)

The number of CD4(+)CD28(null) (CD28(null)) T cells, a unique subset of T lymphocytes with proinflammatory and cell-lytic phenotype, increases markedly in patients with acute coronary syndrome (ACS). ACS patients harboring high numbers of CD28(null) T cells have increased risk of recurrent severe acute coronary events and unfavorable prognosis. The mechanisms that govern the increase in CD28(null) T cells in ACS remain elusive. We investigated whether apoptosis pathways regulating T-cell homeostasis are perturbed in CD28(null) T cells in ACS.We found that CD28(null) T cells in ACS were resistant to apoptosis induction via Fas-ligation or ceramide. This was attributable to a dramatic reduction in proapoptotic molecules Bim, Bax, and Fas in CD28(null) T cells, whereas antiapoptotic molecules Bcl-2 and Bcl-xL were similar in CD28(null) and CD28(+) T cells. We also show that Bim is phosphorylated in CD28(null) T cells and degraded by the proteasome. Moreover, we demonstrate for the first time that proteasomal inhibition restores the apoptosis sensitivity of CD28(null) T cells in ACS.We show that CD28(null) T cells in ACS harbor marked defects in molecules that regulate T-cell apoptosis, which tips the balance in favor of antiapoptotic signals and endows these cells with resistance to apoptosis. We demonstrate that the inhibition of proteasomal activity allows CD28(null) T cells to regain sensitivity to apoptosis. A better understanding of the molecular switches that control the apoptosis sensitivity of CD28(null) T cells may reveal novel strategies for targeted elimination of these T cells in ACS patients.
A crucial role for HVEM and BTLA in preventing intestinal inflammation
Authors: Marcos W. Steinberg, Olga Turovskaya, Raziya B. Shaikh, Gisen Kim, Declan F. McCole, Klaus Pfeffer, Kenneth M. Murphy, Carl F. Ware, Mitchell Kronenberg
Journal: The Journal of Experimental Medicine (2008)

The interaction between the tumor necrosis factor (TNF) family member LIGHT and the TNF family receptor herpes virus entry mediator (HVEM) co-stimulates T cells and promotes inflammation. However, HVEM also triggers inhibitory signals by acting as a ligand that binds to B and T lymphocyte attenuator (BTLA), an immunoglobulin super family member. The contribution of HVEM interacting with these two binding partners in inflammatory processes remains unknown. In this study, we investigated the role of HVEM in the development of colitis induced by the transfer of CD4+CD45RBhigh T cells into recombination activating gene (Rag)−/− mice. Although the absence of HVEM on the donor T cells led to a slight decrease in pathogenesis, surprisingly, the absence of HVEM in the Rag−/− recipients led to the opposite effect, a dramatic acceleration of intestinal inflammation. Furthermore, the critical role of HVEM in preventing colitis acceleration mainly involved HVEM expression by radioresistant cells in the Rag−/− recipients interacting with BTLA. Our experiments emphasize the antiinflammatory role of HVEM and the importance of HVEM expression by innate immune cells in preventing runaway inflammation in the intestine.
The Estimation of the Quality of Potable Waters
Authors: W. L. Lindsay
Journal: BMJ (1876)

I cannot but think that operating is a very senous matter in these cases.I believe the great secret of treatment is, to take the cases early, and not to treat them by extension and counterextension, but to lock the parts thoroughly together.Our object is to give the patient rest, which I do not think he will get by pulling at the limbs, for it must be remembered that we are not dealing witha joint in which the articular surfaces can be separated.I have proceeded on this plan, and I must say that our cases have done very well.
Ferumoxytol for Treating Iron Deficiency Anemia in CKD
Authors: Bruce S. Spinowitz, Annamaria T. Kausz, Jovanna Baptista, Sylvia D. Noble, Renuka Sothinathan, Marializa V. Bernardo, Louis Brenner, Brian J. G. Pereira
Journal: Journal of the American Society of Nephrology (2008)

Iron deficiency is an important cause of anemia in patients with chronic kidney disease (CKD), but intravenous iron is infrequently used among patients who are not on dialysis. Ferumoxytol is a novel intravenous iron product that can be administered as a rapid injection. This Phase III trial randomly assigned 304 patients with CKD in a 3:1 ratio to two 510-mg doses of intravenous ferumoxytol within 5 +/- 3 d or 200 mg of elemental oral iron daily for 21 d. The increase in hemoglobin at day 35, the primary efficacy end point, was 0.82 +/- 1.24 g/dl with ferumoxytol and 0.16 +/- 1.02 g/dl with oral iron (P < 0.0001). Among patients who were not receiving erythropoiesis-stimulating agents, hemoglobin increased 0.62 +/- 1.02 g/dl with ferumoxytol and 0.13 +/- 0.93 g/dl with oral iron. Among patients who were receiving erythropoiesis-stimulating agents, hemoglobin increased 1.16 +/- 1.49 g/dl with ferumoxytol and 0.19 +/- 1.14 g/dl with oral iron. Treatment-related adverse events occurred in 10.6% of patients who were treated with ferumoxytol and 24.0% of those who were treated with oral iron; none was serious. In summary, a regimen of two doses of 510 mg of intravenous ferumoxytol administered rapidly within 5 +/- 3 d was well tolerated and had the intended therapeutic effect. This regimen may offer a new, efficient option to treat iron deficiency anemia in patients with CKD.
Mild cystic fibrosis and normal or borderline sweat test in patients with the 3849 + 10 kb C &amp;rarr; T mutation
Authors: A. Augarten, Y. Yahav, A. Szeinberg, S. Noiman, E. Gazit, B-S. Kerem, Y. Rivlin, A. Tal, H. Blau, L. Ben-Tur, E. Kerem
Journal: The Lancet (1993)
East–West gradient in the incidence of inflammatory bowel disease in Europe: the ECCO-EpiCom inception cohort
Authors: J Burisch, N Pedersen, S Čuković-Čavka, M Brinar, I Kaimakliotis, D Duricova, O Shonová, I Vind, S Avnstrøm, N Thorsgaard, V Andersen, S Krabbe, J F Dahlerup, R Salupere, K R Nielsen, J Olsen, P Manninen, P Collin, E V Tsianos, K H Katsanos, K Ladefoged, L Lakatos, E Björnsson, G Ragnarsson, Y Bailey, S Odes, D Schwartz, M Martinato, G Lupinacci, M Milla, A De Padova, R D'Incà, M Beltrami, L Kupcinskas, G Kiudelis, S Turcan, O Tighineanu, I Mihu, F Magro, L F Barros, A Goldis, D Lazar, E Belousova, I Nikulina, V Hernandez, D Martinez-Ares, S Almer, Y Zhulina, J Halfvarson, N Arebi, S Sebastian, P L Lakatos, E Langholz, P Munkholm
Journal: Gut (2013)

Objective The incidence of inflammatory bowel disease (IBD) is increasing in Eastern Europe. The reasons for these changes remain unknown. The aim of this study was to investigate whether an East–West gradient in the incidence of IBD in Europe exists. Design A prospective, uniformly diagnosed, population based inception cohort of IBD patients in 31 centres from 14 Western and eight Eastern European countries covering a total background population of approximately 10.1 million people was created. One-third of the centres had previous experience with inception cohorts. Patients were entered into a low cost, web based epidemiological database, making participation possible regardless of socioeconomic status and prior experience. Results 1515 patients aged 15 years or older were included, of whom 535 (35%) were diagnosed with Crohn's disease (CD), 813 (54%) with ulcerative colitis (UC) and 167 (11%) with IBD unclassified (IBDU). The overall incidence rate ratios in all Western European centres were 1.9 (95% CI 1.5 to 2.4) for CD and 2.1 (95% CI 1.8 to 2.6) for UC compared with Eastern European centres. The median crude annual incidence rates per 100 000 in 2010 for CD were 6.5 (range 0–10.7) in Western European centres and 3.1 (range 0.4–11.5) in Eastern European centres, for UC 10.8 (range 2.9–31.5) and 4.1 (range 2.4–10.3), respectively, and for IBDU 1.9 (range 0–39.4) and 0 (range 0–1.2), respectively. In Western Europe, 92% of CD, 78% of UC and 74% of IBDU patients had a colonoscopy performed as the diagnostic procedure compared with 90%, 100% and 96%, respectively, in Eastern Europe. 8% of CD and 1% of UC patients in both regions underwent surgery within the first 3 months of the onset of disease. 7% of CD patients and 3% of UC patients from Western Europe received biological treatment as rescue therapy. Of all European CD patients, 20% received only 5-aminosalicylates as induction therapy. Conclusions An East–West gradient in IBD incidence exists in Europe. Among this inception cohort—including indolent and aggressive cases—international guidelines for diagnosis and initial treatment are not being followed uniformly by physicians.
<i>Para</i>-phenylenediamine and allergic sensitization: risk modification by<i>N</i>-acetyltransferase 1 and 2 genotypes
Authors: B. Blömeke, R. Brans, P.-J. Coenraads, H. Dickel, T. Bruckner, D.W. Hein, M. Heesen, H.-F. Merk, Y. Kawakubo
Journal: British Journal of Dermatology (2009)

Para-phenylenediamine (PPD) is a common contact sensitizer causing allergic contact dermatitis, a major skin problem. As PPD may need activation to become immunogenic, the balance between activation and/or detoxification processes may influence an individual's susceptibility. PPD is acetylated and the metabolites do not activate dendritic-like cells and T cells of PPD-sensitized individuals.To investigate whether PPD can be acetylated in vitro by the two N-acetyltransferases 1 (NAT1) and 2 (NAT2). Based on the assumption that N-acetylation by NAT1 or NAT2 is a detoxification reaction with respect to sensitization, we examined whether NAT1 and NAT2 genotypes are different between PPD-sensitized individuals and matched controls.Genotyping for NAT1 and NAT2 polymorphisms was performed in 147 PPD-sensitized individuals and 200 age- and gender-matched controls. Results Both PPD and monoacetyl-PPD were N-acetylated in vitro by recombinant human NAT1 and to a lesser extent by NAT2. Genotyping for NAT1*3, NAT1*4, NAT1*10, NAT1*11 and NAT1*14 showed that genotypes containing the rapid acetylator NAT1*10 allele were under-represented in PPD-sensitized cases (adjusted odds ratio 0.72, 95% confidence interval 0.45-1.16). For NAT2, NAT2*4, NAT2*5AB, NAT2*5C, NAT2*6A and NAT2*7B alleles were genotyped. Individuals homozygous for the rapid acetylator allele NAT2*4 were under-represented in cases compared with controls (4.3% vs. 9.4%), but this trend was not significant.With respect to data indicating that NAT1 but not NAT2 is present in human skin, we conclude that NAT1 genotypes containing the rapid acetylator NAT1*10 allele are potentially associated with reduced susceptibility to PPD sensitization.
Biologically Based Pharmacodynamic Models: Tools for Toxicological Research and Risk Assessment
Authors: R B Conolly, M E Andersen
Journal: The Annual Review of Pharmacology and Toxicology (1991)

The cancer model contains extensive biological detail, but is not fully validated. It is extremely useful for organizing what is known about malignant transformation, for linking measures of tissue dose with biological processes, and for proposing new experiments. It became very clear, as the cancer model was developed, that we lack an adequate understanding of the details of biochemical mechanisms of carcinogen action linking the target-tissue dose of carcinogen with effects on cell birth, death, and mutation rates as specified by the MVK model. This problem extends to noncarcinogenic toxicants such as methotrexate and the organophosphates. In these cases the biologically based descriptions of toxicity stop at the first interaction of the chemical with tissue. The linkage from the primary interaction to ultimate toxic effect is a "black box" that, at present, can only be described empirically rather than in biologically based terms. The models for dioxin and prednisolone do illustrate how biological events several steps removed from the initial tissue interaction of the toxicant can be described in quantitative, biologically based terms. As such they point the way for future development of more realistic descriptions in which the use of purely empirical linkages is reduced. Rigorous organization of current knowledge and specification of a logical sequence of new experiments encompass the major reasons for developing biologically based (structural) descriptions of any process. It bears emphasis that biologically based tissue response models, for cancer, for chloroform cytotoxicity, for functional impairment following organophosphate exposure, etc, are in reality quantitative formulations of an hypothesis or proposed mechanism incorporating the pharmacokinetics of the chemical and the linkage between target-tissue dose and toxic effect(s). The quantitative model allows us to see if the hypothesis is consistent with pertinent data and aids in designing experiments to define, refute, or bolster the general nature of the proposed linkages between tissue dose, tissue response and the whole organism's response to the chemical exposure. In this sense these biologically based models are quantitative descriptions of the current level of understanding of toxic effects in animals. We began this review article by looking at the literature on empirical tissue-response models to educate ourselves on the history of PD modeling. We rapidly found that the clear distinction between PK and PD models described in the literature blurs when one moves to biologically based modeling of tissue disposition and tissue response. Many articles on physiologically based pharmacokinetics turn out on close scrutiny to be as closely related to tissue response as they are to kinetics.(ABSTRACT TRUNCATED AT 400 WORDS)