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Lutz Menzel, Lisa Kleber, Carina Friedrich, Regina Hummel, Larissa Dangel, Jennifer Winter, Katja Schmitz, Irmgard Tegeder, Michael K E Schäfer
In response to traumatic brain injury (TBI) microglia/macrophages and astrocytes release inflammatory mediators with dual effects on secondary brain damage progression. The neurotrophic and anti-inflammatory glycoprotein progranulin (PGRN) attenuates neuronal damage and microglia/macrophage activation in brain injury but mechanisms are still elusive. Here, we studied histopathology, neurology and gene expression of inflammatory markers in PGRN-deficient mice (Grn(-/-) ) 24 h and 5 days after experimental TBI...
October 25, 2016: Glia
Bruna Bellincanta Nicoletto, Thaiana Cirino Krolikowski, Daisy Crispim, Luis Henrique Canani
Progranulin has been recognized as an adipokine related to obesity, insulin resistance and type 2 diabetes mellitus (T2DM). There are scarce data regarding progranulin and kidney disease, but there are some data linking diabetic kidney disease (DKD) and increased progranulin levels. We aimed to better describe the relationship between serum and urinary progranulin levels and DKD in T2DM. This is a case-control study including four groups of subjects: 1) Advanced DKD cases: T2DM patients with estimated glomerular filtration rate (eGFR) <60 mL/min/1...
2016: PloS One
Christine Altmann, Verica Vasic, Stefanie Hardt, Juliana Heidler, Annett Häussler, Ilka Wittig, Mirko H H Schmidt, Irmgard Tegeder
BACKGROUND: Peripheral nerve injury is a frequent cause of lasting motor deficits and chronic pain. Although peripheral nerves are capable of regrowth they often fail to re-innervate target tissues. RESULTS: Using newly generated transgenic mice with inducible neuronal progranulin overexpression we show that progranulin accelerates axonal regrowth, restoration of neuromuscular synapses and recovery of sensory and motor functions after injury of the sciatic nerve...
October 22, 2016: Molecular Neurodegeneration
Liina Kuuluvainen, Minna Pöyhönen, Petra Pasanen, Maija Siitonen, Jaana Rummukainen, Pentti J Tienari, Anders Paetau, Liisa Myllykangas
Mutations in the progranulin (GRN) gene represent about 5-10% of frontotemporal lobar degeneration (FTLD). We describe a proband with a novel GRN mutation c.687T>A, p.(Tyr229*), presenting with dyspraxia, dysgraphia, and dysphasia at the age of 60 and a very severe FTLD neuropathological phenotype with TDP43 inclusions. The nephew of the proband had signs of dementia and personality changes at the age of 60 and showed similar but milder FTLD pathology. Three other family members had had early-onset dementia...
October 20, 2016: Journal of Alzheimer's Disease: JAD
Carlo Wilke, Frank Gillardon, Christian Deuschle, Markus A Hobert, Iris E Jansen, Florian G Metzger, Peter Heutink, Thomas Gasser, Walter Maetzler, Cornelis Blauwendraat, Matthis Synofzik
BACKGROUND AND OBJECTIVE: Reduced progranulin levels are a hallmark of frontotemporal dementia (FTD) caused by loss-of-function (LoF) mutations in the progranulin gene (GRN). However, alterations of central nervous progranulin expression also occur in neurodegenerative disorders unrelated to GRN mutations, such as Alzheimer's disease. We hypothesised that central nervous progranulin levels are also reduced in GRN-negative FTD. METHODS: Progranulin levels were determined in both cerebrospinal fluid (CSF) and serum in 75 subjects (37 FTD patients and 38 controls)...
October 20, 2016: Neuro-degenerative Diseases
Jong-Ho Kim, In-Gu Do, Kyungeun Kim, Jin Hee Sohn, Hong Joo Kim, Woo Kyu Jeon, Sung Ryol Lee, Byung Ho Son, Jun Ho Shin, Heerim Nam, Heon-Ju Kwon, Mi Sung Kim, Hyun Pyo Hong, Ginette Serrero, Dong-Hoe Koo
PURPOSE: Progranulin (PGRN), characterized as an autocrine growth and survival factor, is known to stimulate the proliferation and survival of several cancer cell types. However, little is known about the prognostic role of PGRN in advanced biliary tract cancers (BTCs). METHODS: A retrospective analysis was performed on patients with advanced BTC who received palliative chemotherapy between July 2004 and November 2014. PGRN expression was immunohistochemically evaluated according to staining intensity of tumor and peritumoral cells...
October 15, 2016: Cancer Chemotherapy and Pharmacology
N Wang, J Zhang, J X Yang
Tumor necrosis factor-α (TNF-α) stimulates osteoclast differentiation and suppresses osteoblast differentiation, leading to bone loss and decreased bone mass in local inflammation areas in patients with rheumatoid arthritis. The growth factor progranulin (PGRN) is expressed in various types of cells and play crucial roles in the pathogenesis of atherosclerosis and arthritis by blocking TNF-α. Here, we investigated the role of PGRN in blocking TNF-α-mediated inhibition of osteoblast differentiation and the regulatory mechanism...
September 9, 2016: Genetics and Molecular Research: GMR
Lieke H H Meeter, Holger Patzke, Gordon Loewen, Elise G P Dopper, Yolande A L Pijnenburg, Rick van Minkelen, John C van Swieten
BACKGROUND: Pathogenic mutations in the granulin gene (GRN) are causative in 5-10% of patients with frontotemporal dementia (FTD), mostly leading to reduced progranulin protein (PGRN) levels. Upcoming therapeutic trials focus on enhancing PGRN levels. METHODS: Fluctuations in plasma PGRN (n = 41) and its relationship with cerebrospinal fluid (CSF, n = 32) and specific single nucleotide polymorphisms were investigated in pre- and symptomatic GRN mutation carriers and controls...
May 2016: Dementia and Geriatric Cognitive Disorders Extra
Yanqing Li, Ya Li, Mingfu Ye, Dongyang Wang, Junli Zhao, Xiaohong Sun, Qinwen Mao, Haibin Xia
Progranulin (PGRN), a highly glycosylated, secreted 593 amino acid precursor protein, is a multifunctional molecule that is critical for early embryogenesis, wound repair, inflammatory and tumorigenesis. PGRN can be proteolytically cleaved into seven cysteine-rich granulin (Grn) peptides: G, F, B, A, C, D and E. Both PGRN and its constituent Grn peptides have been implicated in a wide variety of biological activities. However, their functions are far from clear, and the lack of granulin domain-specific antibodies has hindered the progress of the functional study of PGRN and Grns...
September 29, 2016: Protein Expression and Purification
Christine Altmann, Stefanie Hardt, Caroline Fischer, Juliana Heidler, Hee-Young Lim, Annett Häussler, Boris Albuquerque, Béla Zimmer, Christine Möser, Christian Behrends, Frank Koentgen, Ilka Wittig, Mirko H H Schmidt, Albrecht M Clement, Thomas Deller, Irmgard Tegeder
Peripheral or central nerve injury is a frequent cause of chronic pain and the mechanisms are not fully understood. Using newly generated transgenic mice we show that progranulin overexpression in sensory neurons attenuates neuropathic pain after sciatic nerve injury and accelerates nerve healing. A yeast-2-hybrid screen revealed putative interactions of progranulin with autophagy-related proteins, ATG12 and ATG4b. This was supported by colocalization and proteomic studies showing regulations of ATG13 and ATG4b and other members of the autophagy network, lysosomal proteins and proteins involved in endocytosis...
September 11, 2016: Neurobiology of Disease
Elise G P Dopper, Vicky Chalos, Eidrees Ghariq, Tom den Heijer, Anne Hafkemeijer, Lize C Jiskoot, Inge de Koning, Harro Seelaar, Rick van Minkelen, Matthias J P van Osch, Serge A R B Rombouts, John C van Swieten
OBJECTIVE: Frontotemporal dementia (FTD) is characterized by behavioral disturbances and language problems. Familial forms can be caused by genetic defects in microtubule-associated protein tau (MAPT), progranulin (GRN), and C9orf72. In light of upcoming clinical trials with potential disease-modifying agents, the development of sensitive biomarkers to evaluate such agents in the earliest stage of FTD is crucial. In the current longitudinal study we used arterial spin labeling MRI (ASL) in presymptomatic carriers of MAPT and GRN mutations to investigate early changes in cerebral blood flow (CBF)...
2016: NeuroImage: Clinical
Wenjun Yan, Aihao Ding, Ha-Jeong Kim, Hua Zheng, Fang Wei, Xiaojing Ma
Progranulin (PGRN) is a widely expressed, pleiotropic protein that is involved in diverse biological processes, including cellular proliferation, neuron development, and wound healing. However, the role of PGRN in the regulation of pathogen-induced systemic inflammation and the mechanisms involved have not been established. In this study, we show that PGRN-deficient mice display heightened mortality in models of polymicrobial sepsis and endotoxinemia, with increased tissue levels of inflammatory cytokines and reduced IL-10 production...
September 12, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
Simon Molgaard, Ditte Demontis, Alexandra M Nicholson, Nicole A Finch, Ronald C Petersen, Claus M Petersen, Rosa Rademakers, Anders Nykjaer, Simon Glerup
Mutations in progranulin are a major cause of frontotemporal lobe degeneration (FTLD). Hence, plasma progranulin is an attractive biomarker in FTLD but poorly reflects levels in cerebrospinal fluid (CSF), suggesting tissue-specific regulation of progranulin levels. Sortilin was recently identified as a progranulin scavenger receptor that destines it for lysosomal degradation. Proteolysis or alternative splicing generates soluble sortilin variants that retain progranulin binding and potentially functions as a decoy receptor...
November 2016: Experimental Gerontology
J Bełtowski
No abstract text is available yet for this article.
September 8, 2016: Acta Physiologica
Lieke H Meeter, Elise G Dopper, Lize C Jiskoot, Raquel Sanchez-Valle, Caroline Graff, Luisa Benussi, Roberta Ghidoni, Yolande A Pijnenburg, Barbara Borroni, Daniela Galimberti, Robert Jr Laforce, Mario Masellis, Rik Vandenberghe, Isabelle Le Ber, Markus Otto, Rick van Minkelen, Janne M Papma, Serge A Rombouts, Mircea Balasa, Linn Öijerstedt, Vesna Jelic, Katrina M Dick, David M Cash, Sophie R Harding, M Jorge Cardoso, Sebastien Ourselin, Martin N Rossor, Alessandro Padovani, Elio Scarpini, Chiara Fenoglio, Maria C Tartaglia, Foudil Lamari, Christian Barro, Jens Kuhle, Jonathan D Rohrer, Charlotte E Teunissen, John C van Swieten
OBJECTIVE: To evaluate cerebrospinal fluid (CSF) and serum neurofilament light chain (NfL) levels in genetic frontotemporal dementia (FTD) as a potential biomarker in the presymptomatic stage and during the conversion into the symptomatic stage. Additionally, to correlate NfL levels to clinical and neuroimaging parameters. METHODS: In this multicenter case-control study, we investigated CSF NfL in 174 subjects (48 controls, 40 presymptomatic carriers and 86 patients with microtubule-associated protein tau (MAPT), progranulin (GRN), and chromosome 9 open reading frame 72 (C9orf72) mutations), and serum NfL in 118 subjects (39 controls, 44 presymptomatic carriers, 35 patients)...
August 2016: Annals of Clinical and Translational Neurology
Jonathan D Rohrer, Ione O C Woollacott, Katrina M Dick, Emilie Brotherhood, Elizabeth Gordon, Alexander Fellows, Jamie Toombs, Ronald Druyeh, M Jorge Cardoso, Sebastien Ourselin, Jennifer M Nicholas, Niklas Norgren, Simon Mead, Ulf Andreasson, Kaj Blennow, Jonathan M Schott, Nick C Fox, Jason D Warren, Henrik Zetterberg
OBJECTIVE: To investigate serum neurofilament light chain (NfL) concentrations in frontotemporal dementia (FTD) and to see whether they are associated with the severity of disease. METHODS: Serum samples were collected from 74 participants (34 with behavioral variant FTD [bvFTD], 3 with FTD and motor neuron disease and 37 with primary progressive aphasia [PPA]) and 28 healthy controls. Twenty-four of the FTD participants carried a pathogenic mutation in C9orf72 (9), microtubule-associated protein tau (MAPT; 11), or progranulin (GRN; 4)...
September 27, 2016: Neurology
Li Qian, Longlong Lin, Yufeng Du, Xiaoyan Hao, Yuze Zhao, Xuejun Liu
MicroRNAs (miRNAs) have been demonstrated to be critical in regulating tumor development and progression. The present study investigated the expression of miR‑588 using reverse transcription‑quantitative polymerase chain reaction analysis in 85 cases of lung squamous cell carcinoma (SCC), and observed the correlation between the expression of miR‑588 with clinical pathologic features. The results indicated that the expression of miR‑588 was predominantly lower in the tumor samples, compared with non‑tumorous samples, and was negatively associated with tumor stages and lymph node invasion...
October 2016: Molecular Medicine Reports
Sara M G Cioffi, Daniela Galimberti, Federica Barocco, Marco Spallazzi, Chiara Fenoglio, Maria Serpente, Marina Arcaro, Simona Gardini, Elio Scarpini, Paolo Caffarra
Mutations in progranulin gene (GRN) are a common cause of autosomal dominant frontotemporal lobar degeneration syndromes and are associated with a wide phenotypic heterogeneity. The majority of genetic defects in GRN consists of loss-of-function mutations, causing haploinsufficiency, and is associated with extremely low plasma progranulin levels. Herein, we describe a patient who developed language dysfunctions and memory disturbances at 63 years of age. Considering the early onset and the positive family history (sister aged 50 with non-fluent/agrammatic variant of primary progressive aphasia, father with behavioral disturbances in his sixties), a genetic analysis was carried out, showing the presence of a novel mutation [g...
September 6, 2016: Journal of Alzheimer's Disease: JAD
R A Armstrong
Factors associated with survival were studied in 84 neuropathologically documented cases of the pre-senile dementia frontotemporal dementia lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). Kaplan-Meier survival analysis estimated mean survival as 7.9 years (range: 1-19 years, SD = 4.64). Familial and sporadic cases exhibited similar survival, including progranulin (GRN) gene mutation cases. No significant differences in survival were associated with sex, disease onset, Braak disease stage, or disease subtype, but higher survival was associated with lower post-mortem brain weight...
2016: Folia Neuropathologica
Alexandra M Nicholson, Rosa Rademakers
Frontotemporal lobar degeneration is a neurodegenerative disorder affecting over 50,000 people in the United States alone. The most common pathological subtype of FTLD is the presence of ubiquitinated TAR DNA binding protein 43 (TDP-43) accumulations in frontal and temporal brain regions at autopsy. While some cases of FTLD-TDP can be attributed to the inheritance of disease-causing mutations, the majority of cases arise with no known genetic cause. In 2010, the first genome-wide association study was conducted in patients with FTLD-TDP to determine potential genetic risk factors for this homogenous subgroup of dementia patients, leading to the identification of the TMEM106B locus on chromosome 7...
November 2016: Acta Neuropathologica
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