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Jorine de Haan, Johannes V van Thienen, Michael Casaer, Rebekka A Hannivoort, Kristel Van Calsteren, Minke van Tuyl, Mathilde M van Gerwen, Anne Debeer, Frédéric Amant, Rebecca C Painter
Targeted therapies have drastically changed the management of metastatic melanoma and have shown encouraging results on tumour progression but are also known for their high rates of adverse reactions. In general, targeted therapies are contraindicated during pregnancy due to concerns about teratogenesis. For the BRAF V600 inhibitor vemurafenib, the available literature about the effects on human pregnancy is limited to a single case report. In patients with metastatic melanoma that wish to continue their pregnancy, targeted therapies like vemurafenib offer the only possibility of improving maternal outcome...
January 2018: Case Reports in Oncology
Shinju Obara, Tsuyoshi Imaizumi, Takahiro Hakozaki, Atsuyuki Hosono, Yuzo Iseki, Norie Sanbe, Masahiro Murakawa
PURPOSE: Little information is available on the predictive ability of previously published pharmacokinetic models of dexmedetomidine in patients under spinal anesthesia. We evaluated nine published pharmacokinetic models that were constructed in different study settings. METHODS: Sixteen patients received dexmedetomidine infusions after spinal anesthesia according to the manufacturer's recommended regimen (6 µg/kg/h over 10 min followed by 0.2-0.7 µg/kg/h) or target-controlled infusion (initial target of 1...
February 2018: Journal of Anesthesia
P J Colin, L N Hannivoort, D J Eleveld, K M E M Reyntjens, A R Absalom, H E M Vereecke, M M R F Struys
Background: Dexmedetomidine, a selective α 2 -adrenoreceptor agonist, has unique characteristics, with little respiratory depression and rousability during sedations. We characterized the haemodynamic properties of dexmedetomidine by developing a pharmacokinetic-pharmacodynamic (PKPD) model with a focus on changes in mean arterial blood pressure (MAP) and heart rate. Methods: Dexmedetomidine was delivered i.v. to 18 healthy volunteers in a step-up fashion by target-controlled infusion using the Dyck model...
August 1, 2017: British Journal of Anaesthesia
P J Colin, L N Hannivoort, D J Eleveld, K M E M Reyntjens, A R Absalom, H E M Vereecke, M M R F Struys
Background: Dexmedetomidine, a selective α 2 -adrenoreceptor agonist, has unique characteristics, such as maintained respiratory drive and production of arousable sedation. We describe development of a pharmacokinetic-pharmacodynamic model of the sedative properties of dexmedetomidine, taking into account the effect of stimulation on its sedative properties. Methods: In a two-period, randomized study in 18 healthy volunteers, dexmedetomidine was delivered in a step-up fashion by means of target-controlled infusion using the Dyck model...
August 1, 2017: British Journal of Anaesthesia
Maud A S Weerink, Michel M R F Struys, Laura N Hannivoort, Clemens R M Barends, Anthony R Absalom, Pieter Colin
Dexmedetomidine is an α2 -adrenoceptor agonist with sedative, anxiolytic, sympatholytic, and analgesic-sparing effects, and minimal depression of respiratory function. It is potent and highly selective for α2 -receptors with an α2 :α1 ratio of 1620:1. Hemodynamic effects, which include transient hypertension, bradycardia, and hypotension, result from the drug's peripheral vasoconstrictive and sympatholytic properties. Dexmedetomidine exerts its hypnotic action through activation of central pre- and postsynaptic α2 -receptors in the locus coeruleus, thereby inducting a state of unconsciousness similar to natural sleep, with the unique aspect that patients remain easily rousable and cooperative...
August 2017: Clinical Pharmacokinetics
L N Hannivoort, H E M Vereecke, J H Proost, B E K Heyse, D J Eleveld, T W Bouillon, M M R F Struys, M Luginbühl
BACKGROUND: The probability to tolerate laryngoscopy (PTOL) and its derivative, the noxious stimulation response index (NSRI), have been proposed as measures of potency of a propofol-remifentanil drug combination. This study aims at developing a triple drug interaction model to estimate the combined potency of sevoflurane, propofol, and remifentanil in terms of PTOL. We compare the predictive performance of PTOL and the NSRI with various anaesthetic depth monitors. METHODS: Data from three previous studies (n=120) were pooled and reanalysed...
May 2016: British Journal of Anaesthesia
Denise P Veelo, Suzanne S Gisbertz, Rebekka A Hannivoort, Susan van Dieren, Bart F Geerts, Mark I van Berge Henegouwen, Markus W Hollmann
BACKGROUND: Deep muscle relaxation has been shown to facilitate operating conditions during laparoscopic surgery. Minimally invasive esophageal surgery is a high-risk procedure in which the use of deep neuromuscular block (NMB) may improve conditions in the thoracic phase as well. Neuromuscular antagonists can be given on demand or by continuous infusion (deep NMB). However, the positioning of the patient often hampers train-of-four (TOF) monitoring. A continuous infusion thus may result in a deep NMB at the end of surgery...
August 5, 2015: Trials
Laura N Hannivoort, Douglas J Eleveld, Johannes H Proost, Koen M E M Reyntjens, Anthony R Absalom, Hugo E M Vereecke, Michel M R F Struys
BACKGROUND: Several pharmacokinetic models are available for dexmedetomidine, but these have been shown to underestimate plasma concentrations. Most were developed with data from patients during the postoperative phase and/or in intensive care, making them susceptible to errors due to drug interactions. The aim of this study is to improve on existing models using data from healthy volunteers. METHODS: After local ethics committee approval, the authors recruited 18 volunteers, who received a dexmedetomidine target-controlled infusion with increasing target concentrations: 1, 2, 3, 4, 6, and 8 ng/ml, repeated in two sessions, at least 1 week apart...
August 2015: Anesthesiology
Jaap Jan Vos, Marieke Poterman, Laura N Hannivoort, Victor W Renardel De Lavalette, Michel Mrf Struys, Thomas Wl Scheeren, Alain F Kalmar
BACKGROUND: In particular surgical conditions, a balanced anesthesia with a high-antinociceptive contribution is required. This may induce cardiovascular impairment and thus compromise tissue oxygenation. In this prospective observational study, we investigated the hemodynamic stability and tissue oxygen saturation (StO2) in 40 patients with a high-antinociceptive general anesthesia, goal-directed fluid therapy, and norepinephrine. In addition, optimal surgical conditions and safe and fast emergence are pivotal parts of anesthetic management...
2014: Perioperative Medicine
Bjorn Heyse, Johannes H Proost, Laura N Hannivoort, Douglas J Eleveld, Martin Luginbühl, Michel M R F Struys, Hugo E M Vereecke
BACKGROUND: The authors studied the interaction between sevoflurane and remifentanil on bispectral index (BIS), state entropy (SE), response entropy (RE), Composite Variability Index, and Surgical Pleth Index, by using a response surface methodology. The authors also studied the influence of stimulation on this interaction. METHODS: Forty patients received combined concentrations of remifentanil (0 to 12 ng/ml) and sevoflurane (0.5 to 3.5 vol%) according to a crisscross design (160 concentration pairs)...
June 2014: Anesthesiology
Sandra Dunning, Atta Ur Rehman, Marjolein H Tiebosch, Rebekka A Hannivoort, Floris W Haijer, Jannes Woudenberg, Fiona A J van den Heuvel, Manon Buist-Homan, Klaas Nico Faber, Han Moshage
BACKGROUND: In chronic liver disease, hepatic stellate cells (HSCs) are activated, highly proliferative and produce excessive amounts of extracellular matrix, leading to liver fibrosis. Elevated levels of toxic reactive oxygen species (ROS) produced during chronic liver injury have been implicated in this activation process. Therefore, activated hepatic stellate cells need to harbor highly effective anti-oxidants to protect against the toxic effects of ROS. AIM: To investigate the protective mechanisms of activated HSCs against ROS-induced toxicity...
December 2013: Biochimica et Biophysica Acta
Lars P Bechmann, Diana Vetter, Junichi Ishida, Rebekka A Hannivoort, Ursula E Lang, Peri Kocabayoglu, M Isabel Fiel, Ursula Muñoz, Gillian L Patman, Fengxia Ge, Shoshana Yakar, Xiaosong Li, Loranne Agius, Young-Min Lee, Weijia Zhang, Kei Yiu Hui, Despina Televantou, Gary J Schwartz, Derek LeRoith, Paul D Berk, Ryozo Nagai, Toru Suzuki, Helen L Reeves, Scott L Friedman
BACKGROUND & AIMS: Dysregulated glucose homeostasis and lipid accumulation characterize non-alcoholic fatty liver disease (NAFLD), but underlying mechanisms are obscure. We report here that Krüppel-like factor 6 (KLF6), a ubiquitous transcription factor that promotes adipocyte differentiation, also provokes the metabolic abnormalities of NAFLD by post-transcriptionally activating PPARα-signaling. METHODS: Mice with either hepatocyte-specific depletion of KLF6 ('ΔHepKlf6') or global KLF6 heterozygosity (Klf6+/-) were fed a high fat diet (HFD) or chow for 8 or 16 weeks...
May 2013: Journal of Hepatology
Lars P Bechmann, Peri Kocabayoglu, Jan-Peter Sowa, Svenja Sydor, Jan Best, Martin Schlattjan, Anja Beilfuss, Johannes Schmitt, Rebekka A Hannivoort, Alpaslan Kilicarslan, Christian Rust, Frieder Berr, Oliver Tschopp, Guido Gerken, Scott L Friedman, Andreas Geier, Ali Canbay
UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries and may proceed to steatohepatitis (NASH). Apoptosis and free fatty acid (FFA)-induced lipotoxicity are important features of NASH pathogenesis. We have shown a hepatoprotective effect of adiponectin in steatotic livers of hepatitis C virus (HCV) patients and recent data links bile acid (BA) metabolism to the pathogenesis of NAFLD. The aim of this study was to identify potential interactions between BA and FFA metabolism in NAFLD...
April 2013: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
U E Lang, P Kocabayoglu, G Z Cheng, Z Ghiassi-Nejad, U Muñoz, D Vetter, D A Eckstein, R A Hannivoort, M J Walsh, S L Friedman
KLF6, a ubiquitously expressed Krüppel-like transcription factor, is frequently inactivated in human cancer and has significant roles in cellular proliferation, apoptosis, differentiation and development. A key mechanism of KLF6-mediated growth suppression is through p53-independent transactivation of p21. Several cancer-derived KLF6 mutants lead to the loss of p21-mediated growth suppression through an unknown mechanism. Because several colorectal cancer and hepatocellular carcinoma-derived KLF6 mutations affect a glycogen synthase kinase 3β (GSK3β) phosphorylation consensus site, we investigated the role of GSK3β in the regulation of KLF6 function...
September 19, 2013: Oncogene
Úrsula Muñoz, Juan E Puche, Rebekka Hannivoort, Ursula E Lang, Michal Cohen-Naftaly, Scott L Friedman
Alternative splicing of the Krüppel-like factor 6 (KLF6) tumor suppressor into an antagonistic splice variant 1 (SV1) is a pathogenic event in several cancers including hepatocellular carcinoma (HCC) because elevated SV1 is associated with increased tumor metastasis and mortality. Ras activation is one factor that can enhance KLF6 splicing in cancer cells, however pathways driving KLF6 splicing are unknown. Splice site selection is regulated by splice factors that include serine/arginine-rich (SR) proteins such as SRSF1 (ASF-SF2), which in turn is controlled by phosphoinositide 3-kinase (PI3K)/Akt and the mitogen-activated protein kinase (MAPK) signaling pathway...
September 2012: Molecular Cancer Research: MCR
Diana Vetter, Michal Cohen-Naftaly, Augusto Villanueva, Youngmin A Lee, Peri Kocabayoglu, Rebekka Hannivoort, Goutham Narla, Josep M Llovet, Swan N Thung, Scott L Friedman
UNLABELLED: KLF6-SV1 (SV1), the major splice variant of KLF6, antagonizes the KLF6 tumor suppressor by an unknown mechanism. Decreased KLF6 expression in human hepatocellular carcinoma (HCC) correlates with increased mortality, but the contribution of increased SV1 is unknown. We sought to define the impact of SV1 on human outcomes and experimental murine hepatocarcinogenesis and to elucidate its mechanism of action. In hepatitis C virus (HCV)-related HCC, an increased ratio of SV1/KLF6 within the tumor was associated with features of more advanced disease...
October 2012: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Rebekka A Hannivoort, Virginia Hernandez-Gea, Scott L Friedman
Genomics and proteomics have become increasingly important in biomedical science in the past decade, as they provide an opportunity for hypothesis-free experiments that can yield major insights not previously foreseen when scientific and clinical questions are based only on hypothesis-driven approaches. Use of these tools, therefore, opens new avenues for uncovering physiological and pathological pathways. Liver fibrosis is a complex disease provoked by a range of chronic injuries to the liver, among which are viral hepatitis, (non-) alcoholic steatohepatitis and autoimmune disorders...
2012: Fibrogenesis & Tissue Repair
Lars P Bechmann, Rebekka A Hannivoort, Guido Gerken, Gökhan S Hotamisligil, Michael Trauner, Ali Canbay
It is widely known that the liver is a central organ in lipogenesis, gluconeogenesis and cholesterol metabolism. However, over the last decades, a variety of pathological conditions highlighted the importance of metabolic functions within the diseased liver. As observed in Western societies, an increase in the prevalence of obesity and the metabolic syndrome promotes pathophysiological changes that cause non-alcoholic fatty liver disease (NAFLD). NAFLD increases the susceptibility of the liver to acute liver injury and may lead to cirrhosis and hepatocellular cancer...
April 2012: Journal of Hepatology
Lars P Bechmann, Amalia Gastaldelli, Diana Vetter, Gillian L Patman, Laura Pascoe, Rebekka A Hannivoort, Ursula E Lee, Isabel Fiel, Ursula Muñoz, Demetrio Ciociaro, Young-Min Lee, Emma Buzzigoli, Luca Miele, Kei Y Hui, Elisabetta Bugianesi, Alastair D Burt, Christopher P Day, Andrea Mari, Loranne Agius, Mark Walker, Scott L Friedman, Helen L Reeves
UNLABELLED: The polymorphism, KLF6-IVS1-27A, in the Krüppel-like factor 6 (KLF6) transcription factor gene enhances its splicing into antagonistic isoforms and is associated with delayed histological progression of nonalcoholic fatty liver disease (NAFLD). To explore a potential role for KLF6 in the development of insulin resistance, central to NAFLD pathogenesis, we genotyped KLF6-IVS1-27 in healthy subjects and assayed fasting plasma glucose (FPG) and insulin sensitivities. Furthermore, we quantified messenger RNA (mRNA) expression of KLF6 and glucokinase (GCK), as an important mediator of insulin sensitivity, in human livers and in liver tissues derived from a murine Klf6 knockdown model (DeltaKlf6)...
April 2012: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Mirko Tarocchi, Rebekka Hannivoort, Yujin Hoshida, Ursula E Lee, Diana Vetter, Goutham Narla, Augusto Villanueva, Moshe Oren, Josep M Llovet, Scott L Friedman
UNLABELLED: Inactivation of KLF6 is common in hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV) infection, thereby abrogating its normal antiproliferative activity in liver cells. The aim of the study was to evaluate the impact of KLF6 depletion on human HCC and experimental hepatocarcinogenesis in vivo. In patients with surgically resected HCC, reduced tumor expression of KLF6 was associated with decreased survival. Consistent with its role as a tumor suppressor, KLF6+/- mice developed significantly more tumors in response to the chemical carcinogen diethyl nitrosamine (DEN) than wild-type animals...
August 2011: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
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