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Work 1-7 of 7

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Article

The receptor for advanced glycation end products impairs collateral formation in both diabetic and non-diabetic mice

by Laura Hansen; Divya Gupta; Giji Joseph; Daiana Weiss; W Taylor

2016

Subjects
  • Health Sciences, General
  • Engineering, Biomedical
  • File Download
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Abstract:Close

Diabetics often have poor perfusion in their limbs as a result of peripheral artery disease and an impaired ability to generate collateral vessels. The receptor for advanced glycation end products (RAGE) is one protein that is thought to play a detrimental role in collateral development in diabetics due to increased levels of advanced glycation end products (AGE), one of its ligands, in diabetes. Thus, the aim of this study was to investigate the role of RAGE in both diabetic and non-diabetic settings in a model of collateral formation in mice. Streptozotocin was used to induce diabetes in both wild type and RAGE knockout mice. Increased levels of the AGE, N ϵ -(carboxymethyl) lysine (CML), were confirmed via an ELISA. A hindlimb ischemia model, in which the femoral artery is ligated, was used to drive collateral growth and reperfusion was assessed using laser Doppler perfusion imaging and histological analysis of vessels in the muscle. Both of these measurements showed impaired collateral growth in diabetic compared with wild-type mice as well as improved collateral growth in both diabetic and non-diabetic RAGE knockout mice when compared their wild-type counterparts. Distance on a freely accessed running wheel, used as a measure of perfusion recovery, showed that wild-type diabetic mice had functionally impaired recovery compared with their wild-type counterparts. Immunohistochemistry and immunoblotting showed that HMGB-1 (high-mobility group box 1), another RAGE ligand, was increased in the ischemic leg compared with the non-ischemic leg in all mice. This increase in HMGB-1 may explain improvement in animals lacking RAGE and its subsequent signaling. In conclusion, this study shows that RAGE impairs collateral growth in a diabetic setting and also in a non-diabetic setting. This demonstrates the importance of RAGE and alternate RAGE ligands in the setting of collateral vessel growth.

Article

Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients

by Mark R. Rigby; Kristina M. Harris; Ashley Pinckney; Linda A. DiMeglio; Marc S. Rendell; Eric Felner; Jean M. Dostou; Stephen E. Gitelman; Kurt J. Griffin; Eva Tsalikian; Peter A. Gottlieb; Carla J. Greenbaum; Nicole A. Sherry; Wayne V. Moore; Roshanak Monzavi; Steven M. Willi; Philip Raskin; Lynette Keyes-Elstein; S. Alice Long; Sai Kanaparthi; Noha Lim; Deborah Phippard; Carol L. Soppe; Margret L. Fitzgibbon; James McNamara; Gerald T. Nepom; Mario R. Ehlers; T1DAL Study Group

2015

Subjects
  • Health Sciences, General
  • Health Sciences, Immunology
  • Health Sciences, Medicine and Surgery
  • File Download
  • View Abstract

Abstract:Close

BACKGROUND. Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D. METHODS. In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses. RESULTS. A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4+ and CD8+ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1+CD4+ Tem and Tcm (P < 0.01). CONCLUSIONS. In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy. TRIAL REGISTRATION.https://clinicaltrials.gov/ NCT00965458.

Article

Immune history profoundly affects broadly protective B cell responses to influenza

by Sarah F. Andrews; Yunping Huang; Kaval Kaur; Lyubov I. Popova; Irvin Y. Ho; Noel T. Pauli; Carole J. Henry Dunand; William M Taylor; Samuel Lim; Min Huang; Xinyan Qu; Jane-Hwei Lee; Marlene Salgado-Ferrer; Florian Krammer; Peter Palese; Jens Wrammert; Rafi Ahmed; Patrick C. Wilson

2015

Subjects
  • Health Sciences, Immunology
  • Health Sciences, Pharmacology
  • Health Sciences, General
  • File Download
  • View Abstract

Abstract:Close

Generating a broadly protective influenza vaccine is critical to global health. Understanding how immune memory influences influenza immunity is central to this goal. We undertook an in-depth study of the B cell response to the pandemic 2009 H1N1 vaccine over consecutive years. Analysis of monoclonal antibodies generated from vaccineinduced plasmablasts demonstrated that individuals with low preexisting serological titers to the vaccinating strain generated a broadly reactive, hemagglutinin (HA) stalk-biased response. Higher preexisting serum antibody levels correlated with a strain-specific HA head-dominated response. We demonstrate that this HA head immunodominance encompasses poor accessibility of the HA stalk epitopes. Further, we show polyreactivity of HA stalk-reactive antibodies that could cause counterselection of these cells. Thus, preexisting memory B cells against HA head epitopes predominate, inhibiting a broadly protective response against the HA stalk upon revaccination with similar strains. Consideration of influenza exposure history is critical for new vaccine strategies designed to elicit broadly neutralizing antibodies.

Article

Key regulators of galectin–glycan interactions

by Nourine A. Kamili; Connie M. Arthur; Christian Gerner-Smidt; Eden Tafesse; Anna Blenda; Marcelo Dias-Baruffi; Sean R. Stowell

2016

Subjects
  • Health Sciences, Medicine and Surgery
  • Health Sciences, General
  • File Download
  • View Abstract

Abstract:Close

KGaA, Weinheim Protein–ligand interactions serve as fundamental regulators of numerous biological processes. Among protein–ligand pairs, glycan binding proteins (GBPs) and the glycans they recognize represent unique and highly complex interactions implicated in a broad range of regulatory activities. With few exceptions, cell surface receptors and secreted proteins are heavily glycosylated. As these glycans often represent highly regulatable post-translational modifications, alterations in glycosylation can fundamentally impact GBP recognition. Among GBPs, galectins in particular appear to engage a diverse set of glycan determinants to impact a broad range of biological processes. In this review, we will explore factors that impact galectin activity, including the effect of glycan modification on galectin–glycan interactions.

Article

Screening a large pediatric cohort with GH deficiency for mutations in genes regulating pituitary development and GH secretion: Frequencies, phenotypes and growth outcomes

by Werner F. Blum; Jurgen Klammt; Serge Amselem; Heike M. Pfaeffle; Marie Legendre; Marie-Laure Sobrier; Marie-Pierre Luton; Christopher J. Child; Christine Jones; Alan G. Zimmermann; Charmian A. Quigley; Gordon B. Cutler; Cheri L. Deal; Jan Lebl; Ron G. Rosenfeld; John Parks; Roland W. Pfaeffle

2018

Subjects
  • Health Sciences, General
  • File Download
  • View Abstract

Abstract:Close

Background: Pituitary development and GH secretion are orchestrated by multiple genes including GH1, GHRHR, GLI2, HESX1, LHX3, LHX4, PROP1, POU1F1, and SOX3. We aimed to assess their mutation frequency and clinical relevance in children with severe GH deficiency (GHD). Methods: The Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS; Clinical Trial Registry Number: NCT01088412) was a prospective, open-label, observational research program for pediatric patients receiving GH treatment, conducted in 30 countries between 1999 and 2015. The study included a sub-study to investigate mutations in the genes listed above. PCR products from genomic blood cell DNA were analyzed by Sanger sequencing. DNA variants were classified as pathogenic according to the recommendations of the American College of Medical Genetics and Genomics. Demographic, auxologic, and endocrine data at baseline and during GH treatment were documented and related to the genotyping results. Findings: The analysis comprised 917 patients. In 92 patients (10%) 33 mutations were found, 16 previously described and 17 novel (52%). Mutation carriers were significantly younger, shorter, and more slowly growing than non-carriers. In general, their peak values in GH stimulation tests were very low; however, in 15/77 (20%) patients with GH1, PROP1, and SOX3 mutations they were only moderately diminished (3-6 μg/L). Two patients with a GH1 mutation developed TSH deficiency and one ADH deficiency. Using logistic multi-regression analysis, significant indicators of a mutation were combined pituitary hormone deficiency, greater patient-parent height difference (SDS), low GH peak, and young age. Final height SDS gain in mutation carriers (mean ± SD 3.4 ± 1.4) was greater than in non-carriers (2.0 ± 1.4; P <.001) and in patients with non-GHD short stature. Interpretation: DNA testing for mutations in children with severe GHD shows a positive finding in approximately 10%. Phenotypes of mutation carriers can be variable. The benefit for clinical practice justifies DNA testing as an important component in the diagnostic work-up of patients with severe GHD. Fund: Eli Lilly and Company, Indianapolis, IN, USA. ClinicalTrials.com registration: NCT01088412.

Article

Cytogenetic Risk Determines Outcomes After Allogeneic Transplantation in Older Patients With Acute Myeloid Leukemia in Their Second Complete Remission: A Center for International Blood and Marrow Transplant Research Cohort Analysis

by Fotios V. Michelis; Vikas Gupta; Mei-Jie Zhang; Hai-Lin Wang; Mahmoud Aljurf; Ulrike Bacher; Amer Beitinjaneh; Yi-Bin Chen; Zachariah DeFilipp; Robert Peter Gale; Partow Kebriaei; Mohamed Kharfan-Dabaja; Hillard M. Lazarus; Taiga Nishihori; Richard F. Olsson; Betul Oran; Armin Rashidi; David A. Rizzieri; Martin S. Tallman; Marcos de Lima; H Jean Khoury; Brenda M. Sandmaier; Daniel Weisdorf; Wael Saber

2017

Subjects
  • Health Sciences, Oncology
  • Health Sciences, General
  • File Download
  • View Abstract

Abstract:Close

BACKGROUND: Allogeneic hematopoietic cell transplantation (HCT) offers curative potential to a number of older patients with acute myeloid leukemia (AML) in their first complete remission. However, there are limited data in the literature concerning post-HCT outcomes for older patients in their second complete remission (CR2). METHODS: The purpose of the current study was to retrospectively investigate within the Center for International Blood and Marrow Transplant Research database parameters influencing posttransplant outcomes for patients 60 years of age or older undergoing HCT for AML in CR2. RESULTS: In total, 196 patients from 78 centers were identified; the median age was 64 years (range, 60-78 years). Seventy-one percent had a Karnofsky performance status ≥ 90 at the time of HCT. Reduced-intensity conditioning regimens were used in 159 patients (81%). A univariate analysis demonstrated a 3-year overall survival (OS) rate of 42% (95% confidence interval [CI], 35%-49%), a leukemia-free survival rate of 37% (95% CI, 30%-44%), a cumulative incidence of nonrelapse mortality of 25% (95% CI, 19%-32%), and a cumulative incidence of relapse (CIR) of 38% (95% CI, 31%-45%). A multivariate analysis demonstrated that cytogenetic risk was the only independent risk factor for OS (P =.023) with a hazard ratio (HR) of 1.14 (95% CI, 0.59-2.19) for intermediate-risk cytogenetics and an HR of 2.32 (95% CI, 1.05-5.14) for unfavorable-risk cytogenetics. For CIR, cytogenetic risk was also the only independent prognostic factor (P =.01) with an HR of 1.10 (95% CI, 0.47-2.56) for intermediate-risk cytogenetics and an HR of 2.98 (95% CI, 1.11-8.00) for unfavorable-risk cytogenetics. CONCLUSIONS: Allogeneic HCT is a curative treatment option for older patients with AML in CR2, particularly for those with favorable or intermediate cytogenetic risk. Cancer 2017;123:2035–2042.

Article

Alternative and Natural Therapies for Acute Lung Injury and Acute Respiratory Distress Syndrome

by Vipul J. Patel; Sreeja Biswas Roy; Hiren J. Mehta; Myungsoo Joo; Ruxana T. Sadikot

2018

Subjects
  • Health Sciences, General
  • Health Sciences, Medicine and Surgery
  • File Download
  • View Abstract

Abstract:Close

Introduction. Acute respiratory distress syndrome (ARDS) is a complex clinical syndrome characterized by acute inflammation, microvascular damage, and increased pulmonary vascular and epithelial permeability, frequently resulting in acute respiratory failure and death. Current best practice for ARDS involves "lung-protective ventilation," which entails low tidal volumes and limiting the plateau pressures in mechanically ventilated patients. Although considerable progress has been made in understanding the pathogenesis of ARDS, little progress has been made in the development of specific therapies to combat injury and inflammation. Areas Covered. In recent years, several natural products have been studied in experimental models and have been shown to inhibit multiple inflammatory pathways associated with acute lung injury and ARDS at a molecular level. Because of the pleiotropic effects of these agents, many of them also activate antioxidant pathways through nuclear factor erythroid-related factor 2, thereby targeting multiple pathways. Several of these agents are prescribed for treatment of inflammatory conditions in the Asian subcontinent and have shown to be relatively safe. Expert Commentary. Here we review natural remedies shown to attenuate lung injury and inflammation in experimental models. Translational human studies in patients with ARDS may facilitate treatment of this devastating disease.
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