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CAR T cells directed against CSPG4 limit the growth of brain tumors in cultured neurospheres and glioma xenograft mouse models, with no signs of immune escape owing to loss of antigen expression.
March 14, 2018: Cancer Discovery
Priyanka Sharma, Sonja Ludwig, Laurent Muller, Chang Sook Hong, John M Kirkwood, Soldano Ferrone, Theresa L Whiteside
Tumour-derived exosomes (TEX) are a subset of extracellular vesicles (EVs) present in body fluids of patients with cancer. The role of this exosome subset in melanoma progression has been of interest ever since ex vivo studies of exosomes produced by melanoma cell lines were shown to suppress anti-melanoma immune responses. To study the impact of melanoma-derived exosomes (MTEX) present in patients' plasma on melanoma progression, isolation of MTEX from total plasma exosomes is necessary. We have developed an immunoaffinity-based method for MTEX capture from plasma of melanoma patients...
2018: Journal of Extracellular Vesicles
Serena Pellegatta, Barbara Savoldo, Natalia Di Ianni, Cristina Corbetta, Yuhui Chen, Monica Patané, Chuang Sun, Bianca Pollo, Soldano Ferrone, Francesco DiMeco, Gaetano Finocchiaro, Gianpietro Dotti
The heterogeneous expression of tumor-associated antigens limits the efficacy of chimeric antigen receptor (CAR)-redirected T cells (CAR-Ts) for the treatment of glioblastoma (GBM). We have found that chondroitin sulfate proteoglycan 4 (CSPG4) is highly expressed in 67% of the GBM specimens with limited heterogeneity. CSPG4 is also expressed on primary GBM-derived cells, grown in vitro as neurospheres (GBM-NS), which recapitulate the histopathology and molecular characteristics of primary GBM. CSPG4.CAR-Ts efficiently controlled the growth of GBM-NS in vitro and in vivo upon intracranial tumor inoculation...
February 28, 2018: Science Translational Medicine
Fengying Tang, Megan S Lord, William B Stallcup, John M Whitelock
Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface proteoglycan highly expressed by tumor, perivascular and oligodendrocyte cells and known to be involved cell adhesion and migration. This study showed that CSPG4 was present as a proteoglycan on the cell surface of two melanoma cell lines, MM200 and Me1007, as well as shed into the conditioned medium. CSPG4 from the two melanoma cell lines differed in the amount of chondroitin sulfate (CS) decoration, as well as the way the protein core was fragmented...
February 15, 2018: Journal of Biochemistry
Valny Martin, Honsa Pavel, Waloschkova Eliska, Matuskova Hana, Kriska Jan, Kirdajova Denisa, Androvic Peter, Valihrach Lukas, Kubista Mikael, Anderova Miroslava
NG2 cells represent precursors of oligodendrocytes under physiological conditions; however, following cerebral ischemia they play an important role in glial scar formation. Here, we compared the expression profiles of oligodendroglial lineage cells, after focal cerebral ischemia (FCI) and in Alzheimer's-like pathology using transgenic mice, which enables genetic fate-mapping of Cspg4-positive NG2 cells and their progeny, based on the expression of red fluorescent protein tdTomato. tdTomato-positive cells possessed the expression profile of NG2 cells and oligodendrocytes; however, based on the expression of cell type-specific genes, we were able to distinguish between them...
February 2, 2018: Glia
Slaven Crnkovic, Leigh M Marsh, Elie El Agha, Robert Voswinckel, Bahil Ghanim, Walter Klepetko, Elvira Stacher-Priehse, Horst Olschewski, Wilhelm Bloch, Saverio Bellusci, Andrea Olschewski, Grazyna Kwapiszewska
Pulmonary vascular remodeling is the main pathological hallmark of pulmonary hypertension disease. We undertook a comprehensive and multilevel approach to investigate the origin of smooth muscle actin-expressing cells in remodeled vessels. Transgenic mice that allow for specific, inducible and permanent labeling of endothelial (Cdh5-tdTomato), smooth muscle (Acta2-, Myh11-tdTomato), pericyte (Cspg4-tdTomato) and fibroblast (Pdgfra-tdTomato) lineages were used to delineate the cellular origins of pulmonary vascular remodeling...
January 23, 2018: Journal of Pathology
Femke M de Vrij, Christian G Bouwkamp, Nilhan Gunhanlar, Guy Shpak, Bas Lendemeijer, Maarouf Baghdadi, Shreekara Gopalakrishna, Mehrnaz Ghazvini, Tracy M Li, Marialuisa Quadri, Simone Olgiati, Guido J Breedveld, Michiel Coesmans, Edwin Mientjes, Ton de Wit, Frans W Verheijen, H Berna Beverloo, Dan Cohen, Rob M Kok, P Roberto Bakker, Aviva Nijburg, Annet T Spijker, P M Judith Haffmans, Erik Hoencamp, Veerle Bergink, Jacob A Vorstman, Timothy Wu, Loes M Olde Loohuis, Najaf Amin, Carolyn D Langen, Albert Hofman, Witte J Hoogendijk, Cornelia M van Duijn, M Arfan Ikram, Meike W Vernooij, Henning Tiemeier, André G Uitterlinden, Ype Elgersma, Ben Distel, Joost Gribnau, Tonya White, Vincenzo Bonifati, Steven A Kushner
Schizophrenia is highly heritable, yet its underlying pathophysiology remains largely unknown. Among the most well-replicated findings in neurobiological studies of schizophrenia are deficits in myelination and white matter integrity; however, direct etiological genetic and cellular evidence has thus far been lacking. Here, we implement a family-based approach for genetic discovery in schizophrenia combined with functional analysis using induced pluripotent stem cells (iPSCs). We observed familial segregation of two rare missense mutations in Chondroitin Sulfate Proteoglycan 4 (CSPG4) (c...
January 4, 2018: Molecular Psychiatry
Shu-Hsuan Claire Hsu, Puviindran Nadesan, Vijitha Puviindran, William B Stallcup, David G Kirsch, Benjamin A Alman
Sarcomas, and the mesenchymal precursor cells from which they arise, express chondroitin sulfate proteoglycan 4 (NG2/CSPG4). However, NG2/CSPG4's function and its capacity to serve as a therapeutic target in this tumor type are unknown. Here, we used cells from human tumors and a genetically engineered autochthonous mouse model of soft-tissue sarcomas (STSs) to determine NG2/CSPG4's role in STS initiation and growth. Inhibiting NG2/CSPG4 expression in established murine and human STSs decreased tumor volume by almost two-thirds and cell proliferation rate by 50%...
February 16, 2018: Journal of Biological Chemistry
Thomas J Stone, Angus Keeley, Alex Virasami, William Harkness, Martin Tisdall, Elisa Izquierdo Delgado, Alice Gutteridge, Tony Brooks, Mark Kristiansen, Jane Chalker, Lisa Wilkhu, William Mifsud, John Apps, Maria Thom, Mike Hubank, Tim Forshew, J Helen Cross, Darren Hargrave, Jonathan Ham, Thomas S Jacques
Glioneuronal tumours are an important cause of treatment-resistant epilepsy. Subtypes of tumour are often poorly discriminated by histological features and may be difficult to diagnose due to a lack of robust diagnostic tools. This is illustrated by marked variability in the reported frequencies across different epilepsy surgical series. To address this, we used DNA methylation arrays and RNA sequencing to assay the methylation and expression profiles within a large cohort of glioneuronal tumours. By adopting a class discovery approach, we were able to identify two distinct groups of glioneuronal tumour, which only partially corresponded to the existing histological classification...
October 20, 2017: Acta Neuropathologica
Michael K E Schäfer, Irmgard Tegeder
Traumatic injury of the central nervous system is one of the leading causes of death and disability in young adults. Failure of regeneration is caused by autonomous neuronal obstacles and by formation of the glial scar, which is essential to seal the injury but also constitutes a barrier for regrowing axons. The scar center is highly inflammatory and populated by NG2+ glia, whereas astrocytes form the sealing border and trap regrowing axons, suggesting that the non-permissive environment of activated astrocytes and extracellular matrix components is one of the reasons for the regenerative failure...
October 17, 2017: Matrix Biology: Journal of the International Society for Matrix Biology
Yoko Egami, Yuta Narushima, Motohiro Ohshima, Akira Yoshida, Naruki Yoneta, Yasufumi Masaki, Kunihiko Itoh
CD antigens are well known as therapeutic targets of B-cell lymphoma. To isolate therapeutic antibodies that recognize novel targets other than CD antigens, we constructed a phage display combinatorial antibody Fab library from bone marrow lymphocytes of B-cell lymphoma patient. To eliminate antibodies reactive with known B-cell lymphoma antigen, non-hematopoietic and patient's sera reactive HeLaS3 cells was selected as a target of whole cell panning. Five rounds of panning against live HeLaS3 cells retrieved single Fab clone, termed AHSA (Antibody to HeLa Surface Antigen)...
September 28, 2017: Journal of Biochemistry
Min Liu, Ping Xu, Zhenlong Guan, Xiaohong Qian, Peter Dockery, Una Fitzgerald, Timothy O'Brien, Sanbing Shen
Brain nerve fibers are insulated by myelin which is produced by oligodendrocytes. Defects in myelination are increasingly recognized as a common pathology underlying neuropsychiatric and neurodevelopmental disorders, which are associated with deletions of the Unc-51-like kinase 4 (ULK4) gene. Key transcription factors have been identified for oligodendrogenesis, but little is known about their associated regulators. Here we report that Ulk4 acts as a key regulator of myelination. Myelination is reduced by half in the Ulk4(tm1a/tm1a) hypomorph brain, whereas expression of axonal marker genes Tubb3, Nefh, Nefl and Nefm remains unaltered...
January 2018: Glia
Jennifer Karmouch, Qiong Q Zhou, Christina Y Miyake, Raffaella Lombardi, Kai Kretzschmar, Marie Bannier-Hélaouët, Hans Clevers, Xander H T Wehrens, James T Willerson, Ali J Marian
RATIONALE: Arrhythmogenic cardiomyopathy is caused primarily by mutations in genes encoding desmosome proteins. Ventricular arrhythmias are the cardinal and typically early manifestations, whereas myocardial fibroadiposis is the pathological hallmark. Homozygous DSP (desmoplakin) and JUP (junction protein plakoglobin) mutations are responsible for a subset of patients with arrhythmogenic cardiomyopathy who exhibit cardiac arrhythmias and dysfunction, palmoplanter keratosis, and hair abnormalities (cardiocutaneous syndromes)...
December 8, 2017: Circulation Research
Xin Yu, Liang Qu, Darell D Bigner, Vidyalakshmi Chandramohan
Chondroitin sulfate proteoglycan 4 (CSPG4) is a promising target for cancer immunotherapy due to its high level of expression in a number of malignant tumors, and its essential role in tumor growth and progression. Clinical application of CSPG4-targeting immunotherapies is hampered by the lack of fully human high-affinity CSPG4 antibodies or antibody fragments. To overcome this limitation, we performed affinity maturation on a novel human CSPG4 single-chain Fv fragment (scFv) using the random mutagenesis approach and screened for improved variants from a yeast display library using a modified whole-cell panning method followed by fluorescence-activated cell sorting...
September 1, 2017: Protein Engineering, Design & Selection: PEDS
Jianqiang Wu, Zhengguang Guo, Youhe Gao
Despite advances in cancer treatments, early diagnosis of cancer is still the most promising way to improve outcomes. Without homeostatic control, urine reflects systemic changes in the body and can potentially be used for early detection of cancer. In this study, a tumor-bearing rat model was established by subcutaneous injection of Walker 256 cells. Urine samples from tumor-bearing rats were collected at five time points during cancer development. Dynamic urine proteomes were profiled using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS)...
November 2017: Cancer Medicine
Alexandra Y Tsidulko, Galina M Kazanskaya, Diana V Kostromskaya, Svetlana V Aidagulova, Roman S Kiselev, Alexandr M Volkov, Vyacheslav V Kobozev, Alexei S Gaitan, Alexei L Krivoshapkin, Elvira V Grigorieva
Neuron-glial antigen 2 (NG2, also known as CSPG4) and hyaluronic acid receptor CD44 are chondroitin sulphate proteoglycans actively involved in brain development and its malignant transformation. Here, we aimed to compare prognostic significances of NG2, CD44 and Ki-67 expression in glioblastoma multiforme patients. Totally, 45 tissue samples and 83 paraffin-embedded tissues for 75 patients were analysed. The prognostic values of the genes were analysed using Kaplan-Meier survival curves. Grade III gliomas showed 2-fold difference in NG2 expression between anaplastic astrocytoma and oligoastrocytoma (10...
September 2017: Tumour Biology: the Journal of the International Society for Oncodevelopmental Biology and Medicine
Josefine Radke, Florian Roßner, Torben Redmer
Melanoma cell expression of the nerve growth factor receptor CD271 is associated with stem-like properties. However, the contributing role of the receptor in melanoma cell migration is elusive. Here, we explored extracranial (skin, soft tissue, lymph node and liver, n = 13) and matched brain metastases (BM, n = 12) and observed a heterogeneous distribution of phenotypically distinct subsets of CD271(+) cells. In addition, we observed that CD271 expression gradually rises along with melanoma progression and metastasis by exploration of publicly available expression data of nevi, primary melanoma (n = 31) and melanoma metastases (n = 54)...
August 29, 2017: Scientific Reports
Pulkit Gupta, Zhifen Zhang, Seiji N Sugiman-Marangos, John Tam, Swetha Raman, Jean-Phillipe Julien, Heather K Kroh, D Borden Lacy, Nicholas Murgolo, Kavitha Bekkari, Alex G Therien, Lorraine D Hernandez, Roman A Melnyk
Clostridium difficile is a major nosocomial pathogen that produces two exotoxins, TcdA and TcdB, with TcdB thought to be the primary determinant in human disease. TcdA and TcdB are large, multidomain proteins, each harboring a cytotoxic glucosyltransferase domain that is delivered into the cytosol from endosomes via a translocation domain after receptor-mediated endocytosis of toxins from the cell surface. Although there are currently no known host cell receptors for TcdA, three cell-surface receptors for TcdB have been identified: CSPG4, NECTIN3, and FZD1/2/7...
October 20, 2017: Journal of Biological Chemistry
Weam Alshenibr, Mustafa M Tashkandi, Saqer F Alsaqer, Yazeed Alkheriji, Amelia Wise, Sadanand Fulzele, Pushkar Mehra, Mary B Goldring, Louis C Gerstenfeld, Manish V Bais
BACKGROUND: Lysyl oxidase like-2 (LOXL2) is a copper-dependent amine oxidase. Our previous studies showed that LOXL2 is elevated during mouse fracture healing. The goal of this study was to evaluate the potential of LOXL2 to act as an anabolic agent in cartilage affected by osteoarthritis (OA). METHODS: LOXL2 was visualized in tissues from human knee and hip joints and temporomandibular joints (TMJ) by immunofluorescence. The activity of LOXL2 in human articular and TMJ chondrocytes was assessed by cell-based assays, microarray analysis, and RT-qPCR, and LOXL2-mediated activation of NF-κB and extracellular signal-related kinase (ERK) signaling pathways was measured by western blotting...
August 2, 2017: Arthritis Research & Therapy
Valeria Rolih, Giuseppina Barutello, Selina Iussich, Raffaella De Maria, Elena Quaglino, Paolo Buracco, Federica Cavallo, Federica Riccardo
Thanks to striking progress in both the understanding of anti-tumor immune response and the characterization of several tumor associated antigens (TAA), a more rational design and more sophisticated strategies for anti-tumor vaccination have been possible. However, the effectiveness of cancer vaccines in clinical trial is still partial, indicating that additional studies are needed to optimize their design and their pre-clinical testing. Indeed, anti-tumor vaccination success relies on the choice of the best TAA to be targeted and on the translational power of the pre-clinical model used to assess its efficacy...
July 1, 2017: Journal of Translational Medicine
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