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Josephine M E Tan, Emma C L Cook, Marlene van den Berg, Saskia Scheij, Noam Zelcer, Anke Loregger
BACKGROUND AND AIMS: Cholesterol is an essential lipid for cellular function and membrane integrity, and hence its cellular levels and distribution must be tightly regulated. Biosynthesis of cholesterol is ramped when its cellular levels are low. Herein, the ER-resident and rate-limiting enzymes 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) and squalene monooxygenase (SQLE) play a prominent role. We have recently reported that MARCH6, an E3 ubiquitin ligase, specifically promotes cholesterol-stimulated ubiquitylation and subsequent proteasomal degradation of SQLE, but not of HMGCR...
December 23, 2018: Atherosclerosis
Manon C A Pronk, Jisca Majolée, Anke Loregger, Jan S M van Bezu, Noam Zelcer, Peter L Hordijk, Igor Kovačević
Rho GTPases control both the actin cytoskeleton and adherens junction stability and are recognized as essential regulators of endothelial barrier function. Rho GTPases act as molecular switches and are primarily regulated by the exchange of GDP and GTP. However, post-translational modifications such as phosphorylation, prenylation and ubiquitination can additionally alter their localization, stability and activity. F-box proteins are involved in the recognition of substrate proteins pre-destined for ubiquitination and subsequent degradation...
January 2, 2019: Molecular Biology of the Cell
E Danielle Sims, Kuan-Wen Wang, Adam Fleming, Donna L Johnston, Shayna M Zelcer, Shahrad Rod Rassekh, Sarah Burrow, Lehana Thabane, M Constantine Samaan
Survivors of childhood brain tumors (SCBT) face a higher risk of cardiometabolic disorders and premature mortality compared to the general population. Excess adiposity is a known risk factor for these comorbidities. However, while SCBT have higher adiposity compared to healthy controls, measuring adiposity in clinical practice involves access to specialized equipment and may impact busy clinical services. Tri-ponderal Mass Index (TMI; kg/m3 ) may be a superior measure of adiposity when compared to Body Mass Index (BMI; kg/m2 )...
November 5, 2018: Scientific Reports
Nienke M van Loon, Patrick C N Rensen, Noam Zelcer
No abstract text is available yet for this article.
October 14, 2018: Aging
Duco Steven Koenis, Lejla Medzikovic, Pieter Bas van Loenen, Michel van Weeghel, Stephan Huveneers, Mariska Vos, Ingrid Johanna Evers-van Gogh, Jan Van den Bossche, Dave Speijer, Yongsoo Kim, Lodewyk Wessels, Noam Zelcer, Wilbert Zwart, Eric Kalkhoven, Carlie Jacoba de Vries
Activation of macrophages by inflammatory stimuli induces reprogramming of mitochondrial metabolism to support the production of pro-inflammatory cytokines and nitric oxide. Hallmarks of this metabolic rewiring are downregulation of α-ketoglutarate formation by isocitrate dehydrogenase (IDH) and accumulation of glutamine-derived succinate, which enhances the inflammatory response via the activity of succinate dehydrogenase (SDH). Here, we identify the nuclear receptor Nur77 (Nr4a1) as a key upstream transcriptional regulator of this pro-inflammatory metabolic switch in macrophages...
August 21, 2018: Cell Reports
Anthony Alioui, Julie Dufour, Valerio Leoni, Anke Loregger, Martina Moeton, Luigi Iuliano, Chiara Zerbinati, Amandine Septier, Pierre Val, Allan Fouache, Vincenzo Russo, David H Volle, Jean-Marc A Lobaccaro, Noam Zelcer, Silvère Baron
This paper has been retracted at the request of the authors.
July 4, 2018: Nature Communications
Nienke M van Loon, Roelof Ottenhoff, Sander Kooijman, Martina Moeton, Saskia Scheij, Reinout L P Roscam Abbing, Marion J J Gijbels, Johannes H M Levels, Vincenzo Sorrentino, Jimmy F P Berbée, Patrick C N Rensen, Noam Zelcer
Objective- The E3 ubiquitin ligase IDOL (inducible degrader of the LDLR [LDL (low-density lipoprotein) receptor]) is a post-transcriptional regulator of LDLR abundance. Model systems and human genetics support a role for IDOL in regulating circulating LDL levels. Whether IDOL plays a broader metabolic role and affects development of metabolic syndrome-associated comorbidities is unknown. Approach and Results- We studied WT (wild type) and Idol(-/-) (Idol-KO) mice in 2 models: physiological aging and diet-induced obesity...
August 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Donna L Johnston, Daniel Keene, Douglas Strother, Maria Taneva, Lucie Lafay-Cousin, Chris Fryer, Katrin Scheinemann, Anne-Sophie Carret, Adam Fleming, Samina Afzal, Beverly Wilson, Lynette Bowes, Shayna Zelcer, Chris Mpofu, Mariana Silva, Valerie Larouche, Josee Brossard, Eric Bouffet
Medulloblastoma is the most common malignant brain tumor in children. Published survival rates for this tumor are ∼70%; however, there is limited published information on outcome after disease recurrence. This was an observational study which included all persons under the age of 18 years diagnosed with medulloblastoma from 1990 to 2009 inclusive in Canada. Data collected included date of diagnosis, age at diagnosis, sex, stage, pathology, treatment, recurrence, and current status. Survival rates were determined...
April 2018: Journal of Pediatric Hematology/oncology
Kuan-Wen Wang, Russell J de Souza, Adam Fleming, Donna L Johnston, Shayna M Zelcer, Shahrad Rod Rassekh, Sarah Burrow, Lehana Thabane, M Constantine Samaan
Children with brain tumors (CBT) are at higher risk of cardiovascular disease and type 2 diabetes compared to the general population, in which birth weight is a risk factor for these diseases. However, this is not known in CBT. The primary aim of this study was to explore the association between birth weight and body mass measures in CBT, compared to non-cancer controls. This is a secondary data analysis using cross-sectional data from the CanDECIDE study (n = 78 CBT and n = 133 non-cancer controls)...
January 26, 2018: Scientific Reports
Alvaro Lassaletta, Douglas Strother, Normand Laperriere, Juliette Hukin, Magimairajan Issai Vanan, Karen Goddard, Lucie Lafay-Cousin, Donna L Johnston, Shayna Zelcer, Michal Zapotocky, Revathi Rajagopal, Vijay Ramaswamy, Cynthia Hawkins, Uri Tabori, Annie Huang, Ute Bartels, Eric Bouffet
OBJECTIVE: Clinical trials have failed to demonstrate a survival benefit of adjuvant chemotherapy in diffuse intrinsic pontine gliomas (DIPG). Radiation therapy (RT) is the only effective treatment thus far and reirradiation (rRT) has become an option at the time of progression. The aim of this study was to review the Canadian experience of DIPG rRT with a focus on the safety and possible efficacy of this approach. METHOD: We retrospectively reviewed the demographic, clinical, and RT data of patients with DIPG treated in Canada with rRT...
June 2018: Pediatric Blood & Cancer
Anke Loregger-Wiesmann, Matthijs Raaben, Josephine Tan, Saskia Scheij, Martina Moeton, Hela Gelberg, Elmer Stickel, Joseph Roitelman, Thijn Brummelkamp, Noam Zelcer
No abstract text is available yet for this article.
August 2017: Atherosclerosis
Kimberley Widger, Rinku Sutradhar, Adam Rapoport, Christina Vadeboncoeur, Shayna Zelcer, Alisha Kassam, Katherine Nelson, Ying Liu, Joanne Wolfe, Craig C Earle, Jason D Pole, Sumit Gupta
Purpose The impact of specialized pediatric palliative care (SPPC) teams on patterns of end-of-life care is unknown. We sought to determine (1) which children with cancer access SPPC and (2) the impact of accessing SPPC on the risk of experiencing high-intensity end-of-life care (intensive care unit admission, mechanical ventilation, or in-hospital death). Methods Using a provincial childhood cancer registry, we assembled a retrospective cohort of Ontario children with cancer who died between 2000 and 2012 and received care through pediatric institutions with an SPPC team...
March 10, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Liwei Ren, Yuan Sun, Hong Lu, Dien Ye, Lijuan Han, Na Wang, Alan Daugherty, Furong Li, Miaomiao Wang, Fengting Su, Wenjun Tao, Jie Sun, Noam Zelcer, Adam E Mullick, A H Jan Danser, Yizhou Jiang, Yongcheng He, Xiongzhong Ruan, Xifeng Lu
RATIONALE: An elevated level of plasma LDL (low-density lipoprotein) is an established risk factor for cardiovascular disease. Recently, we reported that the (pro)renin receptor ([P]RR) regulates LDL metabolism in vitro via the LDLR (LDL receptor) and SORT1 (sortilin-1), independently of the renin-angiotensin system. OBJECTIVES: To investigate the physiological role of (P)RR in lipid metabolism in vivo. METHODS AND RESULTS: We used N-acetylgalactosamine modified antisense oligonucleotides to specifically inhibit hepatic (P)RR expression in C57BL/6 mice and studied the consequences this has on lipid metabolism...
March 2, 2018: Circulation Research
Sofianne Gabrielli, Ann E Clarke, Harley Eisman, Judy Morris, Lawrence Joseph, Sebastien La Vieille, Peter Small, Rodrick Lim, Paul Enarson, Michal Zelcer, Edmond S Chan, Chris Mill, Moshe Ben-Shoshan
INTRODUCTION: Data is sparse on drug-induced anaphylaxis (DIA) and there have not been studies assessing the differences in clinical characteristics and management of DIA between adults and children. OBJECTIVE: We assessed the percentage, diagnosis, and management of DIA among all anaphylaxis visits in three pediatric and one adult emergency departments (ED) across Canada. METHODS: Children presenting to the Montreal Children's Hospital (MCH), British Columbia Children's Hospital (BCCH), and Children's Hospital at London Health Sciences Center and adults presenting to Hôpital du Sacré-Coeur with anaphylaxis were recruited as part of the Cross-Canada Anaphylaxis Registry...
March 2018: Immunity, Inflammation and Disease
K-W Wang, A Fleming, D L Johnston, S M Zelcer, S R Rassekh, S Ladhani, A Socha, J Shinuda, S Jaber, S Burrow, S K Singh, L Banfield, R J de Souza, L Thabane, M C Samaan
Survivors of childhood brain tumours (SCBT) have increased cardiometabolic risks, but the determinants of these risks are unclear. This systematic review aims to compare the prevalence of overweight and obesity as well as adiposity measures between SCBT and non-cancer controls. The PubMed, EMBASE, MEDLINE, CINAHL and the Cochrane Library databases were searched. The primary outcomes were the prevalence of overweight and obesity based on body mass index. The secondary outcomes were adiposity measures including percent fat mass, waist-to-hip and waist-to-height ratios...
February 2018: Clinical Obesity
Anke Loregger, Matthijs Raaben, Josephine Tan, Saskia Scheij, Martina Moeton, Marlene van den Berg, Hila Gelberg-Etel, Elmer Stickel, Joseph Roitelman, Thijn Brummelkamp, Noam Zelcer
OBJECTIVE: The cellular demand for cholesterol requires control of its biosynthesis by the mevalonate pathway. Regulation of HMGCR (3-hydroxy-3-methylglutaryl coenzyme A reductase), a rate-limiting enzyme in this pathway and the target of statins, is a key control point herein. Accordingly, HMGCR is subject to negative and positive regulation. In particular, the ability of oxysterols and intermediates of the mevalonate pathway to stimulate its proteasomal degradation is an exquisite example of metabolically controlled feedback regulation...
November 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
Anthony Alioui, Julie Dufour, Valerio Leoni, Anke Loregger, Martina Moeton, Luigi Iuliano, Chiara Zerbinati, Amandine Septier, Pierre Val, Allan Fouache, Vincenzo Russo, David H Volle, Jean-Marc A Lobaccaro, Noam Zelcer, Silvère Baron
Advanced prostate cancer (PCa) is a clinical challenge as no curative therapeutic is available. In this context, a better understanding of metastasis and resistance mechanisms in PCa is an important issue. As phosphatase and tensin homolog (PTEN) loss is the most common genetic lesion in such cancer, we investigate human data sets for mechanisms that can constrain cancer evolution in this setting. Here we report a liver X receptor (LXR) signature, which tightly correlates with PTEN loss, in PCa. Accordingly, the LXR pathway is deregulated in prostate carcinomas in Pten-null mice...
September 5, 2017: Nature Communications
Pooja Panwalkar, Jonathan Clark, Vijay Ramaswamy, Debra Hawes, Fusheng Yang, Christopher Dunham, Stephen Yip, Juliette Hukin, Yilun Sun, Matthew J Schipper, Lukas Chavez, Ashley Margol, Melike Pekmezci, Chan Chung, Adam Banda, Jill M Bayliss, Sarah J Curry, Mariarita Santi, Fausto J Rodriguez, Matija Snuderl, Matthias A Karajannis, Amanda M Saratsis, Craig M Horbinski, Anne-Sophie Carret, Beverly Wilson, Donna Johnston, Lucie Lafay-Cousin, Shayna Zelcer, David Eisenstat, Marianna Silva, Katrin Scheinemann, Nada Jabado, P Daniel McNeely, Marcel Kool, Stefan M Pfister, Michael D Taylor, Cynthia Hawkins, Andrey Korshunov, Alexander R Judkins, Sriram Venneti
Posterior fossa ependymomas (EPN_PF) in children comprise two morphologically identical, but biologically distinct tumor entities. Group-A (EPN_PFA) tumors have a poor prognosis and require intensive therapy. In contrast, group-B tumors (EPN_PFB) exhibit excellent prognosis and the current consensus opinion recommends future clinical trials to test the possibility of treatment de-escalation in these patients. Therefore, distinguishing these two tumor subtypes is critical. EPN_PFA and EPN_PFB can be distinguished based on DNA methylation signatures, but these assays are not routinely available...
November 2017: Acta Neuropathologica
Alvaro Lassaletta, Michal Zapotocky, Matthew Mistry, Vijay Ramaswamy, Marion Honnorat, Rahul Krishnatry, Ana Guerreiro Stucklin, Nataliya Zhukova, Anthony Arnoldo, Scott Ryall, Catriona Ling, Tara McKeown, Jim Loukides, Ofelia Cruz, Carmen de Torres, Cheng-Ying Ho, Roger J Packer, Ruth Tatevossian, Ibrahim Qaddoumi, Julie H Harreld, James D Dalton, Jean Mulcahy-Levy, Nicholas Foreman, Matthias A Karajannis, Shiyang Wang, Matija Snuderl, Amulya Nageswara Rao, Caterina Giannini, Mark Kieran, Keith L Ligon, Maria Luisa Garre, Paolo Nozza, Samantha Mascelli, Alessandro Raso, Sabine Mueller, Theodore Nicolaides, Karen Silva, Romain Perbet, Alexandre Vasiljevic, Cécile Faure Conter, Didier Frappaz, Sarah Leary, Courtney Crane, Aden Chan, Ho-Keung Ng, Zhi-Feng Shi, Ying Mao, Elizabeth Finch, David Eisenstat, Bev Wilson, Anne Sophie Carret, Peter Hauser, David Sumerauer, Lenka Krskova, Valerie Larouche, Adam Fleming, Shayna Zelcer, Nada Jabado, James T Rutka, Peter Dirks, Michael D Taylor, Shiyi Chen, Ute Bartels, Annie Huang, David W Ellison, Eric Bouffet, Cynthia Hawkins, Uri Tabori
Purpose BRAF V600E is a potentially highly targetable mutation detected in a subset of pediatric low-grade gliomas (PLGGs). Its biologic and clinical effect within this diverse group of tumors remains unknown. Patients and Methods A combined clinical and genetic institutional study of patients with PLGGs with long-term follow-up was performed (N = 510). Clinical and treatment data of patients with BRAF V600E mutated PLGG (n = 99) were compared with a large international independent cohort of patients with BRAF V600E mutated-PLGG (n = 180)...
September 1, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
Kimberley Widger, Christina Vadeboncoeur, Shayna Zelcer, Ying Liu, Alisha Kassam, Rinku Sutradhar, Adam Rapoport, Katherine Nelson, Joanne Wolfe, Craig Earle, Jason D Pole, Sumit Gupta
BACKGROUND: Population-based research to identify underserviced populations and the impact of palliative care (PC) is limited as the validity of such data to identify PC services is largely unknown. OBJECTIVE: To determine the validity of using such data to identify the involvement of specialized pediatric PC teams among children with cancer. DESIGN: Retrospective cohort. SUBJECTS: Ontario children with cancer who died between 2000 and 2012, received care through a pediatric institution with a specialized PC team and a clinical PC database...
November 2017: Journal of Palliative Medicine
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