tbuckley/cabot-search huggingface dataset:
Abstract 2530: The anticancer kinase inhibitor dovitinib (TKI258/CHIR258) may have multiple modes of action because it also binds DNA and inhibits topoisomerase I and topoisomerase IIα
Authors: Xing Wu, Jack C. Yalowich, Brian Hasinoff
Journal: Cancer Research (2011)

Abstract Dovitinib (TKI258/CHIR258) is a kinase inhibitor in phase II development for the treatment of renal cell carcinoma, advanced breast cancer, and relapsed multiple myeloma. Dovitinib is thought to exert anticancer effects through its binding to and kinase inhibition of fibroblast growth factor receptor 3 (FGFR3). It also strongly inhibits a number of other kinases that are members of the RTK superfamily, including the vascular endothelial growth factor receptor (VEGFR); fibroblast growth factor receptor 1 (FGFR1); platelet-derived growth factor receptor type 3; FMS-like tyrosine kinase 3 (FLT3); stem cell factor receptor (c-KIT) and colony-stimulating factor receptor 1 (CSF1R) all of which may also contribute to its anticancer activity. In terms of its chemical structure dovitinib is a benzimidazole-quinolinone compound. Thus, structurally it resembles the bisbenzimidazole minor groove binding dye Hoechst 33258. Molecular modeling studies of the docking of dovitinib into an X-ray structure of a Hoechst 33258-DNA complex showed that dovitinib could be reasonably accommodated in the minor groove. Dovitinib was shown to bind to DNA by its ability to increase the DNA melting temperature. Changes in the visible absorbance and fluorescence spectrum of dovitinib that occurred upon addition of DNA were also consistent with DNA binding. Because DNA binders are often topoisomerase I and topoisomerase II inhibitors, the ability of dovitinib to inhibit these DNA processing enzymes was also investigated. Dovitinib inhibited both the decatenation activity and the ATPase activity of topoisomerase IIα in the low micromolar concentration range. Dovitinib was also able to stabilize the topoisomerase IIα-cleavage complex and act as a topoisomerase IIα poison with activity comparable to etoposide as measured by its ability to induce formation of linear DNA. Dovitinib was also examined for its ability to increase phosphorylation of H2AX in K562 cells to determine if it could act as a cellular topoisomerase II poison and induce double strand DNA breaks. Dovitinib was also able to inhibit the topoisomerase I-catalyzed relaxation of DNA. In conclusion, the anticancer activity of dovitinib may result not only from its ability to inhibit multiple kinases, but also from its ability to target topoisomerase I and topoisomerase IIα. Support: CIHR and a Canada Research Chair in Drug Development to BBH and an NIH grant (CA090787) to JCY. 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 2530. doi:10.1158/1538-7445.AM2011-2530
OP0066 Can We Really Identify Latent Tuberculosis? Comparison of the Performance of Tuberculin Skin Test and Interferon Gamma Release Assay before Anti-TNF Therapy: A Systematic Review and Meta-Analysis
Authors: M. Locci, F. Erny, F. Barchechat-Flaisler, J.-L. Leroux, C. Gaujoux Viala
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Current guidelines recommend screening for latent tuberculosis infection prior the introduction of anti-tumor necrosis factor therapy. However, many patients are already taking immunosuppressive therapy, which can affect current diagnostic tests. <h3>Objectives</h3> Due to the recent introduction of the interferon-gamma release assays (IGRA), we sought to assess their ability to detect latent tuberculosis infections in patients before biological treatment and the impact of immunosuppressive therapy on these new tests. <h3>Methods</h3> MEDLINE, EMBASE and COCHRANE were searched (up to April 2013) to identify studies comparing the performance of interferon-gamma release assays (QuantiFERON QTF, T-SPOT.TB) to Tuberculin Skin Test (TST) in candidates for anti TNF treatment, with inflammatory bowel disease or rheumatic disease. The agreement between different tests was described by kappas. In each trial, the odds ratios (OR) were determined to assess the impact of treatment effect on the tests positivity. Where possible, pooled OR were calculated by meta-analysis methodology, using the Mantel-Haenszel method. In case of statistical heterogeneity,all meta-analyses were carried out using random-effects models. <h3>Results</h3> On 533 studies, 45 studies (n=9226 patients) were included for analysis. The agreement between IDR/IGRA was poor. Kappas between QTF and TST were calculated in 18 studies, ranging from 0.03 to 0.52: poor in 15 studies (&lt;0.4) and moderate in 3 studies (0.4-0.6). Kappas between T-SPOT and TST were calculated in 7 studies, ranging from 0.13 to 0.40: poor in 6 studies and moderate in 1 study. Moreover, the agreement between the two IGRA was moderate. Kappas ranged from 0.28 to 0.71 in 8 studies: poor in 1 study, moderate in 5 studies and good in only 2 studies. Immunosuppressive therapy did not significantly influence positive QTF results (7 studies-pooled OR 0.86, 95% CI 0.64-1.15) and positive T-SPOT results (4 studies-pooled OR 0.89, IC 95% 0.63-1.26). In contrast, the corticotherapy significantly reduced the rate of T-SPOT + (2 studies- pooled OR: 0.45, IC 95% 0.23-0.89) and almost significantly reduced the rate of QTF + (3 studies- pooled OR:0.63, IC 95% 0.38-1.02). <h3>Conclusions</h3> The screening of latent tuberculosis raises concerns, especially due to the lack of agreement between IGRA. The impact of immunosuppressive therapy on IGRA was not significant whereas corticotherapy significantly decreased the rate of IGRA positivity. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.5452
Correction of Leukocyte Function in Chediak-Higashi Syndrome by Ascorbate
Authors: Laurence A. Boxer, August M. Watanabe, Manfred Rister, Henry R. Besch, John Allen, Robert L. Baehner
Journal: New England Journal of Medicine (1976)

Because ascorbate potentiates chemotaxis of normal leukocytes, we examined the effect of ascorbate on polymorphonuclear leukocytes from a patient with the Chediak-Higashi syndrome. Chemotactic migration was 104+/-16 leukocytes per 10 fields (mean+/-S.D.) initially and 258+/-44 (P less than 0.001) after ascorbate, as compared to 182+/-10 in controls. There was no bactericidal activity by 40 minutes in the patient's untreated leukocytes. After ascorbate bactericidal activity of patient and untreated control cells was the same. The addition of ascorbate reduced cAMP levels in the patient's cells from a mean of 34.5 pmoles per 10(7) polymorphonuclear leukocytes to 5.9, as compared to a control value of 3.1+/-1.4. The association of elevated cAMP and impaired function in the polymorphonuclear leukocytes of patients with the Chediak-Higashi syndrome may be related to abnormal microtubular assembly.
Aspirin's Next Conquest: Does It Prevent Colon Cancer?
Authors: K. Smigel
Journal: JNCI Journal of the National Cancer Institute (1994)

Journal Article Aspirin's Next Conquest: Does It Prevent Colon Cancer? Get access Kara Smigel Kara Smigel Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 86, Issue 3, 2 February 1994, Pages 166–168, https://doi.org/10.1093/jnci/86.3.166 Published: 02 February 1994
NI-81 * DIFFUSION MR IMAGING GENOMIC FEATURES IDENTIFIES GENOMIC TARGETS INVOLVED IN INVASION AND POOR PROGNOSIS
Authors: E. Wassal, G. Thomas, P. Zinn, R. Colen
Journal: Neuro-Oncology (2014)

PURPOSE:To create an imaging genomic map, linking MR imaging traits with gene and miRNA expression profiles,in GBM patients to determine genomic correlates of diffusion radiophenotype to find new genomic targets. Decreases in diffusion in GBM,is associated with increased cellular density and higher nuclear to cytoplasm ratio.Here,we present the first study examining in a quantitative way MRI-diffusion genomics in GBM to determine targetable genomic biomarkers in GBM. MATERIALS AND METHODS: We identified 80 treatment-naive GBM patients from The Cancer Genome Atlas(TCGA)who had both gene and miRNA expression profiles and pretreatment MR-neuroimaging specifically ADC maps. Image segmentation analysis was done in Slicer 3.6 using segmentation module,Fluid-Attenuated Inversion Recovery(FLAIR)was used for segmentation of the edema and post-contrast T1 weighted-imaging(T1WI)for segmentation of enhancement and necrosis.Diffusion was analyzed in Olea Sphere 2.3 and Conventional FLAIR/post contrast T1WI was registered to DWI/ADC maps.ADC,FLAIR,T1 Gadolinium enhancement values were measured using the ROI based method,in the peri-tumoral edema/non-enhancing tumor and the enhancing tumor zones,dividing the peri-tumoral edema/non-enhancing tumor into 3 zones each of 1 cm width,3 ROI measurements were taken from each zone.Multiple quantitative imaging features were identified and combined to create the imaging biomarker signature predictive for the invasion and poor prognosis of the tumor. All the genomic data was also analyzed to determine the most upregulated mRNAs/miRNAs using ingenuity pathway analysis(IPA) in those with restricted diffusion. RESULTS: Quantitative ADC values were in high correlation with biologically concordant functional genomic targets predicting the invasiveness and progression. CONCLUSIONS: The diffusion and conventional MR radiophenotype identified genes and miRNAs and corresponding molecular networks that were highly associated with tumor invasion.By these means we were able to identify possible key genes and miRNAs involved in the latter regulation.
Early referral for foot ulcers is vital, finds audit of diabetes care
Authors: Jacqui Wise
Journal: BMJ (2016)

A diabetes foot care audit in England and Wales shows that patients who are expertly assessed within two weeks are more likely to be free of foot ulcers at 12 weeks than those who have to wait longer for assessment.1

The National Diabetes Foot Care Audit included 5215 patients presenting with a diabetic foot ulcer to 129 specialist foot care services from July 2014 to April 2015. Most (3699) had been referred by their GP or other health service, and …
Serum Antibody to Double-Stranded RNA and DNA in Patients with Idiopathic and Secondary Uveitis
Authors: Wallace V. Epstein, Margaret Tan, Michael Easterbrook
Journal: New England Journal of Medicine (1971)

To determine whether products of the reaction of uveitis appear in the circulation, serums from 150 patients were examined for antibody to double-stranded RNA and DNA. With the use of an assay based on antibody-dependent binding of radioactive polynucleotides to a solid-phase absorbent, the uveitis specimens were found to have levels of antibody higher than normal in 37 per cent with respect to double-stranded RNA and in 24 per cent with respect to double-stranded DNA. Since the specificities of these serum antibodies are similar to those found in patients with systemic lupus erythematosus, some similar immunologic or infectious mechanisms (or both) may characterize the two disorders.
Arterial hemorrhage due to a buried percutaneous endoscopic gastrostomy catheter
Authors: S. Van Weyenberg, R. Lely
Journal: Endoscopy (2013)

A 63-year old man underwent an emergency esophagogastroduodenoscopy because of hematemesis. He had undergone surgery 2 months earlier for a pT4aN3 oropharyngeal carcinoma. This had been followed 4 weeks later by placement of a percutaneous endoscopic gastrostomy (PEG) because of severe oropharyngeal dysphagia.
A Controlled Trial of High-Dose Intravenous Immune Globulin Infusions as Treatment for Dermatomyositis
Authors: M C Dalakas, I Illa, J M Dambrosia, S A Soueidan, D P Stein, C Otero, S T Dinsmore, S McCrosky
Journal: New England Journal of Medicine (1993)

Dermatomyositis is a clinically distinct myopathy characterized by rash and a complement-mediated microangiopathy that results in the destruction of muscle fibers. In some patients the condition becomes resistant to therapy and causes severe physical disabilities.
A3.1 1.25(OH)<sub>2</sub>D<sub>3</sub>Inhibits Th17 Polarisation and RORγt Expression through GATA3-Dependent and -Independent Mechanisms
Authors: W Dankers, JP van Hamburg, AMC Mus, PS Asmawidjaja, OBJ Corneth, F Luk, JPTM van Leeuwen, RW Hendriks, L Boon, EM Colin, E Lubberts
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background and Objectives</h3> Vitamin D has suppressive effects on autoimmune diseases, such as rheumatoid arthritis (RA). Regulation of Th17 cell activity is an important mechanism by which vitamin D exerts these effects. Aside from inhibiting Th17 cytokines and the Th17 transcription factor RoRγ t, vitamin D induces IL-4 and GATA3. Since GATA3 over-expression inhibits experimental Th17-mediated autoimmunity, we studied the contribution of GATA3 in vitamin D-mediated suppression of Th17 polarisation. <h3>Methods</h3> Therefore CD4<sup>+</sup> T cells were sorted from patients with early RA, naïve DBA-1 mice, DBA-1 mice immunised with collagen type II (CII) or naïve CD2-GATA3 transgenic mice and cultured under T helper cell polarising conditions with or without 1.25(OH)<sub>2</sub>D<sub>3</sub>, the active form of vitamin D. <h3>Results</h3> 1.25(OH)<sub>2</sub>D<sub>3</sub> inhibits Th17 polarisation in CD4+ cells from both non-immunised and CII-immunised mice, while up-regulating IL-4 and GATA3 expression. In these cultures, IL-4 inhibition partly reversed the vitamin D-mediated inhibition of Th17 polarisation. Moreover, GATA3 over-expression reduces Th17 differentiation to a lower level than 1.25(OH)<sub>2</sub>D<sub>3</sub>. Interestingly, combining GATA3 over-expression and 1.25(OH)<sub>2</sub>D<sub>3</sub> treatment reduced IL-17A and RoRγ t expression even further. Furthermore, gene-expression analysis showed that NFAT-C2, which is involved in IL-17A production, was down-regulated by 1.25(OH)<sub>2</sub>D<sub>3</sub>. In addition, in T cells from patients with RA, 1.25(OH)<sub>2</sub>D<sub>3</sub> inhibited Th17 cytokine and RORγ t expression and induced IL-4 and GATA3 expression. <h3>Conclusions</h3> These data show that vitamin D-mediated regulation of Th17 polarisation occurs through GATA3-dependent mechanisms, including direct effects on RORγ t expression and IL-4-mediated inhibition of Th17 polarisation. Moreover, GATA3-independent mechanisms are involved that may include modulation of NFAT-C2 expression.
Dissection sous-muqueuse de larges tumeurs sessiles du rectum et du sigmoïde: Résultats d'une expérience monocentrique chez 113 patients
Authors: J Hochberger, E Wedi, J Huppertz, E Kruse, M Delvaux
Journal: Endoscopy (2014)

La dissection sous-muqueuse endoscopique (ESD) est aujourd'hui reconnue comme un traitement efficace des tumeurs sessiles du rectum et du côlon mais cette technique longue et difficile reste réservée à quelques centres spécialisés. L'ESD permet la résection en un seul bloc de ces tumeurs et donc un examen histologique précis des marges de résection ainsi que de la totalité de la pièce pour évaluer le degré d'invasion de la lésion et le caractère complet de la résection. Dans cette étude nous analysons les indications, conditions techniques de réalisation et résultats cliniques de 116 ESD.
VENTRICULAR ARRHYTHMIAS IN HOSPITALIZED HFPEF PATIENTS
Authors: Madhav Lavu, Ajay Kaja, Arun Kanmantha Reddy, Ravi Thimmisetty, Vimalkumar Veerappan Kandasamy, Claire Hunter, Aryan Mooss, Venkata Alla, Venkata Alla
Journal: Journal of the American College of Cardiology (2015)
Endoscopic ultrasound-guided gastroenterostomy using a lumen-apposing self-expanding metal stent for decompression of afferent loop obstruction
Authors: Pushpak Taunk, Natalie Cosgrove, David Loren, Thomas Kowalski, Ali Siddiqui
Journal: Endoscopy (2015)

Acute afferent loop syndrome following pancreaticoduodenostomy is generally caused by mechanical occlusion due to pancreatic cancer recurrence. Historically, it has been treated with palliative surgical bypass [1] [2] [3] [4] [5]. A retrograde endoscopic approach with placement of an enteral metal stent across the afferent limb stricture is often not possible [2]. We report the first case series of endoscopic ultrasound (EUS)-guided gastrojejunostomy using a lumen-apposing, self-expanding, metal stent (LASEMS) for therapy of acute afferent loop syndrome.
Association between Multiple Cardiovascular Risk Factors and Atherosclerosis in Children and Young Adults
Authors: Gerald S. Berenson, Sathanur R. Srinivasan, Weihang Bao, William P. Newman, Richard E. Tracy, Wendy A. Wattigney
Journal: New England Journal of Medicine (1998)

In adults, cardiovascular risk factors reinforce each other in their effect on cardiovascular events. However, information is scant on the relation of multiple risk factors to the extent of asymptomatic atherosclerosis in young people.
Correction of the Anemia of End-Stage Renal Disease with Recombinant Human Erythropoietin
Authors: Joseph W. Eschbach, Joan C. Egrie, Michael R. Downing, Jeffrey K. Browne, John W. Adamson
Journal: New England Journal of Medicine (1987)

We administered recombinant human erythropoietin to 25 anemic patients with end-stage renal disease who were undergoing hemodialysis. The recombinant human erythropoietin was given intravenously three times weekly after dialysis, and transfusion requirements, hematocrit, ferrokinetics, and reticulocyte responses were monitored. Over a range of doses between 15 and 500 units per kilogram of body weight, dose-dependent increases in effective erythropoiesis were noted. At 500 units per kilogram, changes in the hematocrit of as much as 10 percentage points were seen within three weeks, and increases in ferrokinetics of three to four times basal values, as measured by erythron transferrin uptake, were observed. Of 18 patients receiving effective doses of recombinant human erythropoietin, 12 who had required transfusions no longer needed them, and in 11 the hematocrit increased to 35 percent or more. Along with the rise in hematocrit, four patients had an increase in blood pressure, and a majority had increases in serum creatinine and potassium levels. No organ dysfunction or other toxic effects were observed, and no antibodies to the recombinant hormone were formed. These results demonstrate that recombinant human erythropoietin is effective, can eliminate the need for transfusions with their risks of immunologic sensitization, infection, and iron overload, and can restore the hematocrit to normal in many patients with the anemia of end-stage renal disease. (N Engl J Med 1987; 316: 73–8.)
Abstract 3350: Implications of the STAT6 pathway by interleukin-4 in prostate cancer
Authors: Holger H. Erb, Frédéric R. Santer, Zoran Culig
Journal: Cancer Research (2012)

Abstract Cancer-related inflammation (CRI) can promote or inhibit tumor development, growth and progression. A key role in CRI may be the infiltration of immune cells. During the inflammation process immune cells are recruited to the tumor. They produce cytokines and inflammatory molecules like reactive oxygen and nitrogen species. However, in prostate Cancer (PCa) the role of inflammation is not well understood. Meta-analysis conducted on case-control studies showed an association of prostatitis and the risk of prostate cancer. Moreover, clinical data showed that several cytokines e.g. interleukin (IL)-6, IL-8 and IL-4 are significantly elevated in sera of patients with CRPC. In this study we investigated the role of short-term and long-term IL-4 treatment on the castration resistant prostate cancer lines PC3, Du145 and LNCaP-IL6+. For short-term treatment conditions cells were incubated with increasing concentrations of IL-4 (0.1-10 ng/ml) for 96 h in full growth medium. Neither proliferation rate nor cell-viability of the three cell lines were changed under these conditions. On the other hand, from the known IL-4 downstream targets only phosphorylation of STAT6 was readily detectable after IL-4 treatment, whereas phosphorylation status of the MAP kinases ERK1/2 and AKT was not affected. Among the STAT6 regulated genes only SOCS-1 was upregulated after IL-4 treatment. For long-term treatment conditions PC3, Du145 and LNCaP-IL-6+ cell lines were treated with 5 ng/ml IL-4 over a period of 30 passages. Interestingly, a morphologic change of the PC3 cell line to a more dedifferentiated phenotype was observable after 10 passages of IL-4 treatment and peaked after 20 passages with 30-50% of all cells showing this morphology. In order to evaluate possible effects of IL-4 on stem-cell like phenotype, we analyzed the IL-4 treated PC3 cell line for the presence of stem cell markers CD44, CD133 and integrin α2 by FACS. Indeed, high expression of CD44 and integrin α2 was observable in a subpopulation of PC3 cells. Expression of CD133 was negative due to hypermethylation of the gene. The percentage of marker-positive cells was increasing with passage, showing that IL-4 long-term treatment might be favorable for cells with cancer stem cell-like properties. Collectively, our results show that IL-4 long-term treatment might promote cells with stem cell-like characteristics and therefore influence the progression of the cancerous disease. This work was funded by the European Union FP7 Marie Curie Initial Training Network PRO-NEST. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3350. doi:1538-7445.AM2012-3350
502 LOW PRE-TREATMENT HBSAG PLASMA LEVELS, DURING TREATMENT HBSAG LEVELS DECLINE AND IP-10 CONCENTRATIONS INCREASE PREDICT RESPONSE TO THERAPY IN TOLERANT CHILDREN WITH CHRONIC HEPATITIS B
Authors: I. Carey, M. Horner, M. Bruce, M. Hussain, S. Bansal, D. Vergani, G. Mieli-Vergani
Journal: Journal of Hepatology (2012)
Transvaginal Ultrasonography Compared with Endometrial Biopsy for the Detection of Endometrial Disease
Authors: Robert D. Langer, June J. Pierce, Katherine A. O'Hanlan, Susan R. Johnson, Mark A. Espeland, José F. Trabal, Vanessa M. Barnabei, Maria J. Merino, Robert E. Scully
Journal: New England Journal of Medicine (1997)

Transvaginal ultrasonography is a noninvasive procedure that may be used to detect endometrial disease. However, its usefulness in screening for asymptomatic disease in postmenopausal women before or during treatment with estrogen or estrogen–progesterone replacement is not known.