tbuckley/cabot-search huggingface dataset:
Vedolizumab affects antibody responses to immunisation selectively in the gastrointestinal tract: randomised controlled trial results
Authors: Tim Wyant, Tim Leach, Serap Sankoh, Yuemei Wang, Jonathan Paolino, Marcela F Pasetti, Brian G Feagan, Asit Parikh
Journal: Gut (2014)

<h3>Objective</h3> The α<sub>4</sub>β<sub>7</sub> integrin monoclonal antibody vedolizumab is hypothesised to be gut selective. Effects of vedolizumab on immune responses to parenterally or enterally administered antigens were investigated. <h3>Design</h3> In this randomised, double-blind, placebo-controlled, phase I trial, healthy participants received a single intravenous dose of vedolizumab 750 mg (n=64) or placebo (n=63). After 4 days, participants began intramuscular hepatitis B vaccine (HBV; days 4, 32, 60) and oral cholera vaccine (OCV; days 4, 18) regimens. The study was designed to demonstrate a 15% non-inferiority margin for the between-group difference in the primary end point: percentage of participants with HBV seroconversion at day 74 (serum hepatitis B surface antigen (HBs) antibody titre ≥10 IU/L). OCV seroconversion at day 74 (&gt;4-fold increase in serum cholera toxin (CT) antibodies) was a secondary end point. <h3>Results</h3> A total of 56 (90.3%) placebo-treated and 54 (88.5%) vedolizumab-treated participants responded to HBV. Geometric mean anti-HBs titres were similar for placebo (114.4 IU/L) and vedolizumab (129.6 IU/L) at day 74. A total of 60 (96.8%) placebo-treated and 52 (82.5%) vedolizumab-treated participants responded to OCV at day 74. Geometric mean anti-CT IgG levels were higher for placebo than for vedolizumab at day 74 (9210.08 vs 3007.8 ELISA Units (EU)/mL) and day 32 (11629.3 vs 1575.4 EU/mL). Anti-CT IgA results were similar. Adverse events were consistent with previous experience. One serious adverse event (spontaneous abortion) was reported for placebo. <h3>Conclusions</h3> Vedolizumab did not alter the response to parenterally administered antigens but reduced the response to oral antigens, demonstrating its gut-selective mechanism of action. <h3>Trial registration number</h3> NCT Number: 01981616; EudraCT Number: 2011-001874-24.
Malignant Neoplasms in Long-Term Survivors of Bone Marrow Transplantation
Authors: H. J. Kolb, Gérard Socié, Thomas Duell, Maria Theresa Van Lint, André Tichelli, Jane F. Apperley, Elke Nekolla, Per Ljungman, Niels Jacobsen, M. van Weel, Roland Wick, Melanie Weiss, H. Grant Prentice
Journal: Annals of Internal Medicine (1999)

Background: Patients who receive bone marrow transplants have increased risk for new malignant conditions because of several risk factors, including conditioning with radiation and chemotherapy, immune stimulation, and malignant primary disease. The occurrence of and risk factors for malignant neoplasm in long-term survivors must be assessed. Objective: To determine the risk and define potential risk factors for new malignant conditions in long-term survivors after marrow transplantation. Design: Retrospective multicenter study. Setting: Study of the Late Effects Working Party with 45 transplantation centers cooperating in the European Cooperative Group for Blood and Marrow Transplantation. Patients: 1036 consecutive patients who underwent transplantation for leukemia, lymphoma, inborn diseases of the hematopoietic and immune systems, or severe aplastic anemia. Transplantation was done before December 1985, and patients had survived more than 5 years. Measurements: Reports on malignant neoplasms were evaluated, and the incidence was compared to that in the general population. Patient age and sex, primary disease and status at transplantation, histocompatibility of the donor, conditioning regimen, type of prophylaxis of graft-versus-host disease, development of acute and chronic graft-versus-host disease, and treatment of chronic graft-versus-host disease were evaluated as variables. Results: Median follow-up since transplantation was 10.7 years (range, 5 to 22.1 years). Malignant neoplasms were seen in 53 patients; the actuarial incidence (± SE) was 3.5% ± 0.6% at 10 years and 12.8% ± 2.6% at 15 years. The rate of new malignant disease was 3.8-fold higher than that in an age-matched control population (P < 0.001). The most frequent malignant diseases were neoplasms of the skin (14 patients), oral cavity (7 patients), uterus (including cervix) (5 patients), thyroid gland (5 patients), breast (4 patients), and glial tissue (3 patients). Median age of patients and their donors was 21 years. Malignant neoplasms were more frequent in older patients and in patients with chronic graft-versus-host disease. Older patient age and treatment of chronic graft-versus-host disease with cyclosporine were significant risk factors for new malignant neoplasms after bone marrow transplantation. Conclusions: The spectrum of neoplasms and immunosuppressive treatment with cyclosporine for chronic graft-versus-host disease as dominant risk factors indicate that immunosuppression is the major cause of malignant neoplasms in patients receiving marrow transplants.
Aspartate aminotransferase to platelet ratio and fibrosis‐4 as biomarkers in biopsy‐validated pediatric cystic fibrosis liver disease
Authors: Daniel H. Leung, Mahjabeen Khan, Charles G. Minard, Danielle Guffey, Louise E. Ramm, Andrew D. Clouston, Gregory Miller, Peter J. Lewindon, Ross W. Shepherd, Grant A. Ramm
Journal: Hepatology (2015)

Up to 10% of cystic fibrosis (CF) children develop cirrhosis by the first decade. We evaluated the utility of two simple biomarkers, aspartate aminotransferase to platelet ratio index (APRI) and FIB-4, in predicting degree of fibrosis in pediatric CF liver disease (CFLD) validated by liver biopsy. In this retrospective, cross-sectional study, 67 children with CFLD had dual-pass liver biopsies and 104 age- and sex-matched CF children without liver disease (CFnoLD) had serum to calculate APRI and FIB-4 collected at enrollment. CFLD was defined as having two of the following: (1) hepatomegaly±splenomegaly; (2)>6 months elevation of ALT (>1.5× upper limit of normal ULN); or (3) abnormal liver ultrasound findings. Biopsies were staged according to Metavir classification by two blinded pathologists. Receiver operating characteristic (ROC) analysis and continuation ratio logistic regression were performed to assess the predictability of these biomarkers to distinguish CFLD from CFnoLD and determine fibrosis stage-specific cut-off values. The AUC for APRI was better than FIB-4 (0.75 vs. 0.60; P=0.005) for predicting CFLD and severe CFLD (F3-F4) (0.81). An APRI score>0.264 demonstrated a sensitivity (95% confidence interval [CI]) of 73.1% (60.9, 83.2) and specificity of 70.2% (60.4, 78.8) in predicting CFLD. A 50% increase in APRI was associated with a 2.4-fold (95% CI: 1.7, 3.3) increased odds of having CFLD. APRI demonstrated full agreement with histology staging 37% of the time, but was within one stage 73% of the time. Only FIB-4 predicted portal hypertension at diagnosis (area under the receiver operator characteristic curve [AUC 0.91; P<0.001).This is the first liver biopsy-validated study of APRI and FIB-4 in pediatric CFLD. APRI appears superior to FIB-4 in differentiating CFLD versus CFnoLD. APRI also exhibited a high AUC in predicting severe liver fibrosis with specific cutoffs for lower stages.
HIGHER 30-DAY READMISSION RATE FOR SUSPICION OF ACS: EFFECT OF KIDNEY FUNCTION
Authors: Enoch Arhinful, Xin Xu, Ruth Aguiar, James Bowen, Angela DiSabatino, Michael Stillabower, Doralisa Morrone, William Weintraub, Claudine Jurkovitz
Journal: Journal of the American College of Cardiology (2013)
Response to: ‘Bivalent HPV vaccine safety depending on subtypes of juvenile idiopathic arthritis’ by Dr Akioka
Authors: M W Heijstek, N M Wulffraat
Journal: Annals of the Rheumatic Diseases (2014)

We thank Dr Akioka for the comments1 on our recent study on the bivalent human papillomavirus (HPV) vaccine in patients with juvenile idiopathic arthritis (JIA).2 Akioka and coworkers describe a patient with enthesitis-related JIA after receiving the bivalent HPV vaccine. It was unclear whether this patient newly developed JIA or experienced a flare of pre-existing JIA.

With regard to the former, vaccinations are indeed often described as potential environmental triggers inducing autoimmune diseases in genetically susceptible individuals.3 ,4 For example, cases of systemic lupus erythematosus have been described after the quadrivalent HPV vaccine.5 However, in a large register-based cohort study, including 997 585 girls among whom 296 826 received a total of 696 420 quadrivalent HPV vaccine doses, no association between exposure to the quadrivalent HPV vaccine and autoimmune adverse events was found.6 Thus, large controlled studies often do not support a relation between vaccinations and the induction of autoimmune …
Promising Therapeutic Targets in Neuroblastoma
Authors: Katherine K. Matthay, Rani E. George, Alice L. Yu
Journal: Clinical Cancer Research (2012)

Abstract Neuroblastoma, the most common extracranial solid tumor in children, is derived from neural crest cells. Nearly half of patients present with metastatic disease and have a 5-year event-free survival of &amp;lt;50%. New approaches with targeted therapy may improve efficacy without increased toxicity. In this review we evaluate 3 promising targeted therapies: (i) 131I-metaiodobenzylguanidine (MIBG), a radiopharmaceutical that is taken up by human norepinephrine transporter (hNET), which is expressed in 90% of neuroblastomas; (ii) immunotherapy with monoclonal antibodies targeting the GD2 ganglioside, which is expressed on 98% of neuroblastoma cells; and (iii) inhibitors of anaplastic lymphoma kinase (ALK), a tyrosine kinase that is mutated or amplified in ∼10% of neuroblastomas and expressed on the surface of most neuroblastoma cells. Early-phase trials have confirmed the activity of 131I-MIBG in relapsed neuroblastoma, with response rates of ∼30%, but the technical aspects of administering large amounts of radioactivity in young children and limited access to this agent have hindered its incorporation into treatment of newly diagnosed patients. Anti-GD2 antibodies have also shown activity in relapsed disease, and a recent phase III randomized trial showed a significant improvement in event-free survival for patients receiving chimeric anti-GD2 (ch14.18) combined with cytokines and isotretinoin after myeloablative consolidation therapy. A recently approved small-molecule inhibitor of ALK has shown promising preclinical activity for neuroblastoma and is currently in phase I and II trials. This is the first agent directed to a specific mutation in neuroblastoma, and marks a new step toward personalized therapy for neuroblastoma. Further clinical development of targeted treatments offers new hope for children with neuroblastoma. Clin Cancer Res; 18(10); 2740–53. ©2012 AACR.
Verocytotoxin inhibits mitogenesis and protein synthesis in purified human glomerular mesangial cells without affecting cell viability
Authors: P A Van Setten, V W van Hinsbergh, L P Van den Heuvel, T J van der Velden, N C van de Kar, R J Krebbers, M A Karmali, L A Monnens
Journal: Journal of the American Society of Nephrology (1997)

Acute renal failure is one of the hallmarks of the hemolytic uremic syndrome (HUS). Infection with a verocytotoxin (VT)- or Shiga-like toxin (SLT)-producing Escherichia coli has been strongly implicated in the etiology of the epidemic form of HUS. The functional receptor for these closely related toxins appears to be a glycosphingolipid, globotriaosylceramide (Gb3). Endothelial damage in the glomeruli and arterioles of the kidney induced by VT is believed to play a crucial role in the pathogenesis of HUS. However, little information is available regarding the effects of VT on mesangial cells, which also play an important role in glomerular function. In this study, the effects of VT on human mesangial cells in vitro were investigated. Mesangial cells were enriched by collecting hillock-shaped outgrowths derived from adult human glomeruli and subsequently purified by elimination of contaminating epithelial cells by immunoseparation with ulex europaeus lectin-I (UEA-I)-coated dynabeads. The obtained and subcultured mesangial cell populations were >98% pure. Their mesangial nature was established by the presence of a-smooth muscle cell actin in highly confluent cultures and the absence of cytokeratin or platelet/endothelial cell adhesion molecule-1. Mesangial cells bound VT to bands of Gb3 and a closely related glycolipid, which is similar to a glycolipid involved in the VT-dependent cytokine production in monocytes. VT did not induce the release of cytokines or chemokines in mesangial cells. In VT-susceptible cells, binding of VT to Gb3 causes cell death by the inhibition of protein synthesis. Although protein synthesis was inhibited in mesangial cells, all cells remained viable, both under basal and tumor necrosis factor-alpha-stimulated conditions. However, the marked reduction in protein synthesis may impair a proper response of the cells in conditions of increased demand of newly synthesized proteins. Furthermore, VT markedly inhibited DNA synthesis and proliferation of mesangial cells. The inhibition of mitogenesis was also found with the B-subunit of VT-1 alone, albeit to a lesser extent, without a significant effect on protein synthesis. Because the inhibition of protein synthesis involves the A-subunit, this suggests that two distinct mechanisms contribute to the effects of VT on protein synthesis and mitogenesis. Intracellular routing of VT (A- and B-subunits) may vary between cell types and result in differential effects on human mesangial cells when compared with other cell types.
Aberrant DNA methylation associated with aggressiveness of gastrointestinal stromal tumour
Authors: Yasuyuki Okamoto, Akira Sawaki, Seiji Ito, Toshirou Nishida, Tsuyoshi Takahashi, Minoru Toyota, Hiromu Suzuki, Yasuhisa Shinomura, Ichiro Takeuchi, Keiko Shinjo, Byonggu An, Hidemi Ito, Kenji Yamao, Makiko Fujii, Hideki Murakami, Hirotaka Osada, Hiromi Kataoka, Takashi Joh, Yoshitaka Sekido, Yutaka Kondo
Journal: Gut (2011)

<h3>Background and aims</h3> The majority of gastrointestinal stromal tumors (GISTs) have <i>KIT</i> mutations; however, epigenetic abnormalities that could conceivably potentiate the aggressiveness of GISTs are largely unidentified. Our aim was to establish epigenetic profiles associated with the malignant transformation of GISTs. <h3>Methods</h3> Methylation of four tumor suppressor genes, <i>RASSF1A, p16, CDH1, and MGMT</i> was analyzed in GISTs. Additionally, genome-wide DNA methylation profiles were compared between small, malignant-prone, and malignant GISTs using methylated GpG island amplification microarrays (MCAM) in a training set (n=40). Relationships between the methylation status of genes identified by MCAM and clinical features of the disease were tested in a validation set (n=75). <h3>Results</h3> Methylation of <i>RASSF1A</i> progressively increased from small to malignant GISTs. <i>p16</i> was specifically methylated in malignant-prone and malignant GISTs. MCAM analysis showed that more genes were methylated in advanced than in small GISTs (average of 473 genes vs 360 genes, respectively, <i>P</i>=0.012). Interestingly, the methylation profile of malignant GISTs was prominently affected by their location. Two genes, <i>REC8</i> and <i>PAX3</i>, which were newly-identified via MCAM analysis, were differentially methylated in small and malignant GISTs in the training and validation sets. Patients with methylation of at least <i>REC8</i>, <i>PAX3</i>, or <i>p16</i> had a significantly poorer prognosis (<i>P</i>=0.034). <h3>Conclusion</h3> Our results suggest that GIST is not, in epigenetic terms, a uniform disease and that DNA methylation in a set of genes is associated with aggressive clinical behavior and unfavorable prognosis. The genes identified may potentially serve as biomarkers for predicting aggressive GISTs with poor survivability.
Gastro-oesophageal reflux in mechanically ventilated patients: effects of an oesophageal balloon
Authors: M. Orozco-Levi, M. Félez, E. Martínez-Miralles, J.F. Solsona, M.L. Blanco, J.M. Broquetas, A. Torres
Journal: European Respiratory Journal (2003)

Gastro-oesophageal reflux (GOR) and bronchoaspiration of gastric content are risk factors linked with ventilator-associated pneumonia. This study was aimed at evaluating the effect of a nasogastric tube (NGT) incorporating a low-pressure oesophageal balloon on GOR and bronchoaspiration in patients receiving mechanical ventilation. Fourteen patients were studied in a semi-recumbent position for 2 consecutive days. Inflation or deflation of the oesophageal balloon was randomised. Samples of blood, gastric content, and oropharyngeal and bronchial secretions were taken every 2 h over a period of 8 h. A radioactively labelled nutritional solution was continuously administered through the NGT. The magnitude of both the GOR and bronchoaspiration was measured by radioactivity counting of oropharyngeal and bronchial secretion samples, respectively. Inflation of the oesophageal balloon resulted in a significant decrease of both GOR and bronchoaspiration of gastric content. This protective effect was statistically significant from 4 h following inflation throughout the duration of the study. This study demonstrates that an inflated oesophageal balloon delays and decreases gastro-oesophageal and bronchial aspiration of gastric content in patients carrying a nasogastric tube and receiving enteral nutrition during mechanical ventilation. Although the method was found to be safe when applied for 8 h, longer times should be considered with caution.
Advanced bronchioloalveolar carcinoma: a phase II trial of paclitaxel by 96-hour infusion (SWOG 9714): a Southwest Oncology Group study
Authors: H.L. West, J.J. Crowley, R.B. Vance, W.A. Franklin, R.B. Livingston, S.R. Dakhil, J.K. Giguere, S.E. Rivkin, M. Kraut, K. Chansky, D.R. Gandara
Journal: Annals of Oncology (2005)
Current treatment options and biology of peritoneal mesothelioma: meeting summary of the first NIH peritoneal mesothelioma conference
Authors: R. Hassan, R. Alexander, K. Antman, P. Boffetta, A. Churg, D. Coit, P. Hausner, R. Kennedy, H. Kindler, M. Metintas, L. Mutti, M. Onda, H. Pass, A. Premkumar, V. Roggli, D. Sterman, P. Sugarbaker, R. Taub, C. Verschraegen
Journal: Annals of Oncology (2006)
Calcimimetic Compound Upregulates Decreased Calcium-Sensing Receptor Expression Level in Parathyroid Glands of Rats with Chronic Renal Insufficiency
Authors: Masahide Mizobuchi, Ikuji Hatamura, Hiroaki Ogata, Fumie Saji, Susumu Uda, Kazuhiro Shiizaki, Toshifumi Sakaguchi, Shigeo Negi, Eriko Kinugasa, Shozo Koshikawa, Tadao Akizawa
Journal: Journal of the American Society of Nephrology (2004)

The reduced expression level of the calcium-sensing receptor (CaR) is attributed to the hyposensitivity of parathyroid cells to extracellular calcium concentration [Ca2+]o, which plays a crucial role in the pathogenesis of secondary hyperparathyroidism (SHPT) in patients and rats with chronic renal insufficiency (CRI). Calcimimetic compounds have been demonstrated to improve the decreased sensitivity of CaR to extracellular calcium concentration and to suppress both parathyroid hormone (PTH) oversecretion and parathyroid cell proliferation. However, the effect of calcimimetics on the reduced CaR expression level in parathyroid cells in CRI remains unclarified. The aim of this investigation was to examine the effect of the calcimimetic compound NSP R-568 (R-568) on the CaR expression in the parathyroid cells of rats with experimental CRI. Subtotally nephrectomized rats were fed a high-phosphorus diet for 8 (n = 12; Nx-8 group) or 9 wk (n = 11; Nx-9 group) to induce severe SHPT. Another group of uremic rats were fed a high-phosphorus diet for 8 wk and then orally administered R-568 (100 μmol/kg body wt) once a day for 7 d (n = 11; Nx+R-568 group). Sham-operated rats that were fed a standard diet for 9 wk were used as controls (n = 8). R-568 treatment induced a significant reduction in plasma PTH level with significant decrease in serum calcium and without change in serum phosphorus concentration. Serum 1,25(OH)2D3 level was not affected by R-568 administration. CaR mRNA and protein levels in the Nx-8 and Nx-9 groups significantly decreased compared with those in the controls; however, no significant difference in these parameters was observed between the Nx-8 and Nx-9 groups. In the Nx+R-568 group, CaR mRNA and protein levels significantly increased compared with those in either the Nx-8 or Nx-9 group. R-568 was effective in reducing the number of proliferating cell nuclear antigen–positive cells along with parathyroid gland growth suppression in the Nx+R-568 group compared with that in the Nx-9 group. The results suggest that the calcimimetic compound R-568 upregulates decreased CaR expression, and the upregulation possibly has an enhancement effect on PTH secretion and parathyroid cell hyperplasia through the improved sensitivity of CaR to [Ca2+]o.
TNF-related apoptosis inducing ligand (TRAIL) as a potential response marker for interferon-beta treatment in multiple sclerosis
Authors: Klaus-Peter Wandinger, Jan D Lünemann, Oliver Wengert, Judith Bellmann-Strobl, Orhan Aktas, Alexandra Weber, Eva Grundström, Stefan Ehrlich, Klaus-D Wernecke, Hans-Dieter Volk, Frauke Zipp
Journal: The Lancet (2003)
Fibrosis with Inflammation at One Year Predicts Transplant Functional Decline
Authors: Walter D. Park, Matthew D. Griffin, Lynn D. Cornell, Fernando G. Cosio, Mark D. Stegall
Journal: Journal of the American Society of Nephrology (2010)

Lack of knowledge regarding specific causes for late loss of kidney transplants hampers improvements in long-term allograft survival. Kidney transplants with both interstitial fibrosis and subclinical inflammation but not fibrosis alone after 1 year have reduced survival. This study tested whether fibrosis with inflammation at 1 year associates with decline of renal function in a low-risk cohort and characterized the nature of the inflammation. We studied 151 living-donor, tacrolimus/mycophenolate-treated recipients without overt risk factors for reduced graft survival. Transplants with normal histology (n = 86) or fibrosis alone (n = 45) on 1-year protocol biopsy had stable renal function between 1 and 5 years, whereas those with both fibrosis and inflammation (n = 20) exhibited a decline in GFR and reduced graft survival. Immunohistochemistry confirmed increased interstitial T cells and macrophages/dendritic cells in the group with both fibrosis and inflammation, and there was increased expression of transcripts related to innate and cognate immunity. Pathway- and pathologic process–specific analyses of microarray profiles revealed that potentially damaging immunologic activities were enriched among the overexpressed transcripts (e.g., Toll-like receptor signaling, antigen presentation/dendritic cell maturation, IFN-γ–inducible response, cytotoxic T lymphocyte–associated and acute rejection–associated genes). Therefore, the combination of fibrosis and inflammation in 1-year protocol biopsies associates with reduced graft function and survival as well as a rejection-like gene expression signature, even among recipients with no clinical risk factors for poor outcomes. Early interventions aimed at altering rejection-like inflammation may improve long-term survival of kidney allografts.