Division Research

Amsterdam, Netherlands

Division Research

Amsterdam, Netherlands
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Jones H.,Baylor Scott and oWhite Digestive Disease Research Center | Alpini G.,Division Research | Alpini G.,Baylor Scott and oWhite Digestive Disease Research Center | Alpini G.,Texas A&M University | And 3 more authors.
Acta Pharmaceutica Sinica B | Year: 2015

This review focuses on various components of bile acid signaling in relation to cholangiocytes. Their roles as targets for potential therapies for cholangiopathies are also explored. While many factors are involved in these complex signaling pathways, this review emphasizes the roles of transmembrane G protein coupled receptor (TGR5), farnesoid X receptor (FXR), ursodeoxycholic acid (UDCA) and the bicarbonate umbrella. Following a general background on cholangiocytes and bile acids, we will expand the review and include sections that are most recently known (within 5-7 years) regarding the field of bile acid signaling and cholangiocyte function. These findings all demonstrate that bile acids influence biliary functions which can, in turn, regulate the cholangiocyte response during pathological events. © 2015 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences.


Trzonkowski P.,Medical University of Gdańsk | Bacchetta R.,Stanford University | Battaglia M.,Instituto di Ricovero e Cura A Carattere Scientif Co IRCCS San Raf Aele Scientif C Institute | Berglund D.,Uppsala University | And 20 more authors.
Science Translational Medicine | Year: 2015

Improper activation of the immune system contributes to a variety of clinical conditions, including autoimmune and allergic diseases as well as solid organ and bone marrow transplantation. One approach to counteract this activation is through adoptive therapy with regulatory T cells (Tregs). Ef orts to manufacture these cells have led to good manufacturing practice-compliant protocols, and Treg products are entering early clinical trials. Here, we report the stance of the European Union Cooperation in Science and Technology Action BM1305, "Action to Focus and Accelerate Cell-based Toleranceinducing Therapies-A FACTT?," which identif es hurdles hindering Treg clinical applications in Europe and provides possible solutions.


Zhang B.,Vanderbilt Epidemiology Center | Shu X.-O.,Vanderbilt Epidemiology Center | Delahanty R.J.,Vanderbilt Epidemiology Center | Zeng C.,Vanderbilt Epidemiology Center | And 194 more authors.
Journal of the National Cancer Institute | Year: 2015

Background: Epidemiological studies have linked adult height with breast cancer risk in women. However, the magnitude of the association, particularly by subtypes of breast cancer, has not been established. Furthermore, the mechanisms of the association remain unclear. Methods: We performed a meta-analysis to investigate associations between height and breast cancer risk using data from 159 prospective cohorts totaling 5 216 302 women, including 113 178 events. In a consortium with individual-level data from 46 325 case patients and 42 482 control subjects, we conducted a Mendelian randomization analysis using a genetic score that comprised 168 height-associated variants as an instrument. This association was further evaluated in a second consortium using summary statistics data from 16 003 case patients and 41 335 control subjects. Results: The pooled relative risk of breast cancer was 1.17 (95% confidence interval [CI] = 1.15 to 1.19) per 10 cm increase in height in the meta-analysis of prospective studies. In Mendelian randomization analysis, the odds ratio of breast cancer per 10 cm increase in genetically predicted height was 1.22 (95% CI = 1.13 to 1.32) in the first consortium and 1.21 (95% CI = 1.05 to 1.39) in the second consortium. The association was found in both premenopausal and postmenopausal women but restricted to hormone receptor-positive breast cancer. Analyses of height-associated variants identified eight new loci associated with breast cancer risk after adjusting for multiple comparisons, including three loci at 1q21.2, DNAJC27, and CCDC91 at genome-wide significance level P < 5 × 10-8. Conclusions: Our study provides strong evidence that adult height is a risk factor for breast cancer in women and certain genetic factors and biological pathways affecting adult height have an important role in the etiology of breast cancer. © The Author 2015. Published by Oxford University Press. All rights reserved.


Eilander H.J.,Division Research | Van Heugten C.M.,Maastricht University | Wijnen V.J.M.,Division Research | Croon M.A.,University of Tilburg | De Kort P.L.M.,Stelisabeth Hospital
Journal of Pediatric Rehabilitation Medicine | Year: 2013

AIMS: To explore the course of recovery of consciousness and factors predicting the outcome of severe brain injury with a prolonged period of unconsciousness in children and young adults receiving a specialized rehabilitation treatment, the Early Intensive Neurorehabilitation Programme (EINP). METHODS: A cohort of forty-four patients aged 1.6-25.5 years (M=16.0) with traumatic acquired brain injury (TBI) or non-traumatic acquired brain injury (nTBI) were examined using the Western Neuro Sensory Stimulation Profile every two weeks, from the application for EINP until discharge. The level of consciousness was assessed with the Post-Acute Level of Consciousness Scale, and the level of disability was determined by the Disability Rating Scale. Long-term level of disability of all TBI patients (N=32) was assessed between 2.0 and 4.4 years after discharge from EINP. RESULTS: Two-thirds of all patients recovered to consciousness. Three recovery patterns were identified: remaining in a vegetative state (VS), slow recovery of consciousness, and fast recovery of consciousness. In the long-term, 11 of the TBI patients were severely disabled, 13 were moderately disabled, and 4 were mildly disabled. All TBI patients who were in VS at discharge either had deceased, or recovered to a very severely disabled state. CONCLUSIONS: Three recovery patterns identified in an early stage after starting EINP made it possible to predict long-term level of disability. © 2013 - IOS Press and the authors. All rights reserved.


Slot E.,Division Research | Janssen M.P.,Sanquin Blood Supply Foundation | Marijt-Van Der Kreek T.,Division Research | Zaaijer H.L.,Division Research | And 4 more authors.
Transfusion | Year: 2016

BACKGROUND Risk behavior-based donor selection procedures are widely used to mitigate the risk of transfusion-transmissible infections (TTIs), but their effectiveness is disputed in countries with low residual risks of TTIs. STUDY DESIGN AND METHODS In 1995 to 2014, Dutch blood donors infected with hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV), or syphilis were interviewed by trained medical counselors to identify risk factors associated with TTIs. Trends in the prevalence and incidence of TTIs were analyzed using binomial regression models. RESULTS A total of 972 new donors and 381 repeat donors had TTIs. New donors had higher rates of TTIs compared to repeat donors. Although the HBV and HCV prevalence gradually decreased over time, the incidence of all five TTIs remained stable during the past two decades. In new donors the TTIs had the following risk profiles: "blood-blood contact" for HCV, "unprotected sex" for HIV and syphilis, and "country of birth" for HBV and HTLV. In infected repeat donors, sexual risk factors predominated for all TTIs. At posttest counseling, 28% of infected repeat donors admitted to risk factors leading to permanent donor exclusion if revealed during the donor selection procedure (predominantly male-to-male sex and recent diagnosis of syphilis). CONCLUSION The prevalence and incidence of TTIs among Dutch blood donors are six- to 60-fold lower than in the general Dutch population, illustrating the effectiveness of donor selection procedures. However, at least a quarter of infected donors appeared noncompliant to the donor health questionnaire (DHQ), suggesting that DHQs, or the way donor questioning is implemented, can be improved. © 2015 AABB.


PubMed | Division Research
Type: Journal Article | Journal: American journal of physiology. Gastrointestinal and liver physiology | Year: 2011

Cholangiocarcinoma (CCA) is a devastating biliary cancer. Melatonin is synthesized in the pineal gland and peripheral organs from serotonin by two enzymes, serotonin N-acetyltransferase (AANAT) and acetylserotonin O-methyltransferase (ASMT). Cholangiocytes secrete neuroendocrine factors, including serotonin-regulating CCA growth by autocrine mechanisms. Melatonin exerts its effects by interaction with melatonin receptor type 1A/1B (MT1/MT2) receptors. We propose that 1) in CCA, there is decreased expression of AANAT and ASMT and secretion of melatonin, changes that stimulate CCA growth; and 2) in vitro overexpression of AANAT decreases CCA growth. We evaluated the 1) expression of AANAT, ASMT, melatonin, and MT1/MT2 in human nonmalignant and CCA lines and control and CCA biopsy samples; 2) melatonin levels in nonmalignant and CCA lines, and bile and serum from controls and patients with intrahepatic CCA; 3) effect of melatonin on the growth and expression of AANAT/ASMT and MT1/MT2 in CCA lines implanted into nude mice; and 4) effect of AANAT overexpression on the proliferation, apoptosis, and expression of MT1/MT2 in Mz-ChA-1 cells. The expression of AANAT, ASMT, and melatonin decreased, whereas MT1/MT2 expression increased in CCA lines and biopsy samples. Melatonin secretion decreased in the supernatant of CCA lines and bile of CCA patients. Melatonin decreased xenograft CCA tumor growth in nude mice by increased AANAT/ASMT and melatonin, along with reduced MT1/MT2 expression. Overexpression of AANAT in Mz-ChA-1 cells inhibited proliferation and MT1/MT2 expression and increased apoptosis. There is dysregulation of the AANAT/ASMT/melatonin melatonin receptor axis in CCA, which inhibited melatonin secretion and subsequently enhanced CCA growth.


PubMed | Division Research and Sanquin Blood Supply Foundation
Type: Journal Article | Journal: Transfusion | Year: 2016

Risk behavior-based donor selection procedures are widely used to mitigate the risk of transfusion-transmissible infections (TTIs), but their effectiveness is disputed in countries with low residual risks of TTIs.In 1995 to 2014, Dutch blood donors infected with hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV), or syphilis were interviewed by trained medical counselors to identify risk factors associated with TTIs. Trends in the prevalence and incidence of TTIs were analyzed using binomial regression models.A total of 972 new donors and 381 repeat donors had TTIs. New donors had higher rates of TTIs compared to repeat donors. Although the HBV and HCV prevalence gradually decreased over time, the incidence of all five TTIs remained stable during the past two decades. In new donors the TTIs had the following risk profiles: blood-blood contact for HCV, unprotected sex for HIV and syphilis, and country of birth for HBV and HTLV. In infected repeat donors, sexual risk factors predominated for all TTIs. At posttest counseling, 28% of infected repeat donors admitted to risk factors leading to permanent donor exclusion if revealed during the donor selection procedure (predominantly male-to-male sex and recent diagnosis of syphilis).The prevalence and incidence of TTIs among Dutch blood donors are six- to 60-fold lower than in the general Dutch population, illustrating the effectiveness of donor selection procedures. However, at least a quarter of infected donors appeared noncompliant to the donor health questionnaire (DHQ), suggesting that DHQs, or the way donor questioning is implemented, can be improved.

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