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Bischof, J.; Westhoff, M.-A.; Wagner, J.E.; Halatsch, M.-E.; Trentmann, S.; Knippschild, U.; Wirtz, C.R.; Burster, T. |
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Cancer stem cells: The potential role of autophagy, proteolysis, and cathepsins in glioblastoma stem cells |
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Journal Article |
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2017 |
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Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine |
Abbreviated Journal |
Tumour Biol |
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39 |
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3 |
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1010428317692227 |
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Animals; Autophagy; Brain Neoplasms/*metabolism/*pathology; Cathepsins/*metabolism; Glioblastoma/*metabolism/*pathology; Humans; Neoplastic Stem Cells/*metabolism/*pathology; Proteolysis; *Major histocompatibility complex class I; *autophagy; *cathepsin; *glioblastoma |
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One major obstacle in cancer therapy is chemoresistance leading to tumor recurrence and metastasis. Cancer stem cells, in particular glioblastoma stem cells, are highly resistant to chemotherapy, radiation, and immune recognition. In case of immune recognition, several survival mechanisms including, regulation of autophagy, proteases, and cell surface major histocompatibility complex class I molecules, are found in glioblastoma stem cells. In different pathways, cathepsins play a crucial role in processing functional proteins that are necessary for several processes and proper cell function. Consequently, strategies targeting these pathways in glioblastoma stem cells are promising approaches to interfere with tumor cell survival and will be discussed in this review. |
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3 Department of Neurosurgery, Surgery Center, Ulm University Medical Center, Ulm University, Ulm, Germany |
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1010-4283 |
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PMID:28347245 |
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Call Number |
ref @ user @ |
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96600 |
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Hira, V.V.V.; Verbovsek, U.; Breznik, B.; Srdic, M.; Novinec, M.; Kakar, H.; Wormer, J.; der Swaan, B.V.; Lenarcic, B.; Juliano, L.; Mehta, S.; Van Noorden, C.J.F.; Lah, T.T. |
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Title |
Cathepsin K cleavage of SDF-1alpha inhibits its chemotactic activity towards glioblastoma stem-like cells |
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Journal Article |
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Year |
2017 |
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Biochimica et Biophysica Acta |
Abbreviated Journal |
Biochim Biophys Acta |
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1864 |
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3 |
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594-603 |
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Amino Acid Sequence; Cathepsin K/genetics/*metabolism; Cell Line, Tumor; Chemokine CXCL12/chemistry/genetics/*metabolism; Chemotaxis; Gene Expression; Heterocyclic Compounds/pharmacology; Humans; Neoplastic Stem Cells/*metabolism/pathology; Neuroglia/*metabolism/pathology; Protein Binding; Protein Conformation, alpha-Helical; Protein Conformation, beta-Strand; Proteolysis; Receptors, CXCR/genetics/metabolism; Receptors, CXCR4/antagonists & inhibitors/genetics/*metabolism; Stem Cell Niche/genetics; *Cathepsin K; *Glioma stem-like cells; *Niche; *Stromal-derived factor-1alpha |
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Glioblastoma (GBM) is the most aggressive primary brain tumor with poor patient survival that is at least partly caused by malignant and therapy-resistant glioma stem-like cells (GSLCs) that are protected in GSLC niches. Previously, we have shown that the chemo-attractant stromal-derived factor-1alpha (SDF-1alpha), its C-X-C receptor type 4 (CXCR4) and the cysteine protease cathepsin K (CatK) are localized in GSLC niches in glioblastoma. Here, we investigated whether SDF-1alpha is a niche factor that through its interactions with CXCR4 and/or its second receptor CXCR7 on GSLCs facilitates their homing to niches. Furthermore, we aimed to prove that SDF-1alpha cleavage by CatK inactivates SDF-1alpha and inhibits the invasion of GSLCs. We performed mass spectrometric analysis of cleavage products of SDF-1alpha after proteolysis by CatK. We demonstrated that CatK cleaves SDF-1alpha at 3 sites in the N-terminus, which is the region of SDF-1alpha that binds to its receptors. Confocal imaging of human GBM tissue sections confirmed co-localization of SDF-1alpha and CatK in GSLC niches. In accordance, 2D and 3D invasion experiments using CXCR4/CXCR7-expressing GSLCs and GBM cells showed that SDF-1alpha had chemotactic activity whereas CatK cleavage products of SDF-1alpha did not. Besides, CXCR4 inhibitor plerixafor inhibited invasion of CXCR4/CXCR7-expressing GSLCs. In conclusion, CatK can cleave and inactivate SDF-1alpha. This implies that CatK activity facilitates migration of GSLCs out of niches. We propose that activation of CatK may be a promising strategy to prevent homing of GSLCs in niches and thus render these cells sensitive to chemotherapy and radiation. |
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Department of Genetic Toxicology and Cancer Biology, National Institute of Biology, Vecna pot 111, 1000 Ljubljana, Slovenia; Jozef Stefan International Postgraduate School, Jamova 39, 1000 Ljubljana, Slovenia; Department of Biochemistry, Faculty of Chemistry and Chemical Engineering, University of Ljubljana, Vecna pot 113, 1000 Ljubljana, Slovenia |
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0006-3002 |
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PMID:28040478 |
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ref @ user @ |
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96615 |
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Li, M.; Xiao, A.; Floyd, D.; Olmez, I.; Lee, J.; Godlewski, J.; Bronisz, A.; Bhat, K.P.L.; Sulman, E.P.; Nakano, I.; Purow, B. |
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CDK4/6 inhibition is more active against the glioblastoma proneural subtype |
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Journal Article |
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Year |
2017 |
Publication |
Oncotarget |
Abbreviated Journal |
Oncotarget |
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Volume |
8 |
Issue |
33 |
Pages |
55319-55331 |
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Cdk4/6; glioblastoma; mesenchymal; palbociclib; proneural |
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Glioblastoma (GBM) is the most common and lethal brain tumor. Gene expression profiling has classified GBM into distinct subtypes, including proneural, mesenchymal, and classical, and identifying therapeutic vulnerabilities of these subtypes is an extremely high priority. We leveraged The Cancer Genome Atlas (TCGA) data, in particular for microRNA expression, to seek druggable core pathways in GBM. The E2F1-regulated miR-17 92 cluster and its analogs are shown to be highly expressed in proneural GBM and in GSC lines, suggesting the E2F cell cycle pathway might be a key driver in proneural GBM. Consistently, CDK4/6 inhibition with palbociclib preferentially inhibited cell proliferation in vitro in a majority of proneural GSCs versus those of other subtypes. Palbociclib treatment significantly prolonged survival of mice with established intracranial xenografts of a proneural GSC line. We show that most of these sensitive PN GSCs expressed higher levels of CDK6 and had intact Rb1, while two GSC lines with CDK4 overexpression and null Rb1 were highly resistant to palbociclib. Importantly, palbociclib treatment of proneural GSCs upregulated mesenchymal-associated markers and downregulated proneural-associated markers, suggesting that CDK4/6 inhibition induced proneural-mesenchymal transition and underscoring the enhanced role of the E2F cell cycle pathway in the proneural subtype. Lastly, the combination of palbociclib and N,N-diethylaminobenzaldehyde, an inhibitor of the mesenchymal driver ALDH1A3, showed strong synergistic inhibitory effects against proneural GSC proliferation. Taken together, our results reveal that proneural GBM has increased vulnerability to CDK4/6 inhibition, and the proneural subtype undergoes dynamic reprogramming upon palbociclib treatment-suggesting the need for a combination therapeutic strategy. |
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Neuro-Oncology Division, Department of Neurology, University of Virginia, Charlottesville, VA, USA |
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1949-2553 |
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PMID:28903422 |
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Call Number |
ref @ user @ |
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96569 |
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Coll, C. de V.N.; Domingues, M.R.; Hallal, P.C.; da Silva, I.C.M.; Bassani, D.G.; Matijasevich, A.; Barros, A.; Santos, I.S.; Bertoldi, A.D. |
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Changes in leisure-time physical activity among Brazilian pregnant women: comparison between two birth cohort studies (2004 – 2015) |
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Journal Article |
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2017 |
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BMC Public Health |
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BMC Public Health |
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17 |
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1 |
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119 |
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Adult; Body Mass Index; Brazil; Cohort Studies; *Exercise; Female; Humans; *Leisure Activities; Maternal Age; Mothers/*statistics & numerical data; Obesity/complications; Parity; Pregnancy; Pregnancy Complications/etiology/*prevention & control; Pregnancy Trimesters/physiology; Time Factors; Young Adult; Birth cohort studies; Exercise; Motor activity; Physical activity; Pregnancy; Recommendations; Surveillance |
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BACKGROUND: Low levels of leisure-time physical activity (LTPA) during pregnancy have been shown in studies conducted worldwide. Surveillance is extremely important to monitor the progress of physical activity patterns over time and set goals for effective interventions to decrease inactivity among pregnant women. The aim of this study was to evaluate time changes in LTPA among Brazilian pregnant women in an 11-year period (2004-2015) by comparing data from two birth cohort studies. METHODS: Two population-based birth cohort studies were carried out in the city of Pelotas, southern Brazil, in 2004 and 2015. A total of 4244 and 4271 mothers were interviewed after delivery. Weekly frequency and duration of each session of LTPA in a typical week were reported for the pre-pregnancy period and for each trimester of pregnancy. Trends in both recommended LTPA (>/=150 min/week) and any LTPA (regardless of weekly amount) were analysed overtime. Changes were also calculated separately for subgroups of maternal age, schooling, family income, parity, pre-pregnancy body mass index and pre-pregnancy LTPA. RESULTS: The proportion of women engaged in recommended levels of LTPA pre-pregnancy increased from 11.2% (95%CI 10.0-12.2) in 2004 to 15.8% (95%CI 14.6-16.9) in 2015. During pregnancy, no changes were observed over the period for the first (10.6 to 10.9%) and second (8.7 to 7.9%) trimesters, whereas there was a decrease from 3.4% (95%CI 2.9-4.0) to 2.4% (95%CI 1.9-2.8) in the last trimester. Major decreases in LTPA in the last trimester were observed among women who were younger, with intermediate to high income, high schooling, primiparous, pre-pregnancy obese and, engaged in LTPA before pregnancy. Changes in any LTPA practice followed the same patterns described for recommended LTPA. CONCLUSIONS: Despite the increase in the proportion of women engaged in LTPA before pregnancy between 2004 and 2005, LTPA levels remained stable during the first and second trimesters of pregnancy and declined during the third gestational trimester over the period. Interventions to encourage the maintenance of LTPA practice throughout pregnancy are urgently needed. |
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Postgraduate Program in Epidemiology, Federal University of Pelotas, Pelotas, Brazil |
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1471-2458 |
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PMID:28122524 |
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ref @ user @ |
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98029 |
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Patino, A.; Alcalde, V.; Gutierrez, C.; Romero, M.G.; Carrillo, A.M.; Vargas, L.E.; Vallejo, C.E.; Zarama, V.; Mora Rodriguez, J.L.; Bustos, Y.; Granada, J.; Aguiar, L.G.; Menendez, S.; Cohen, J.I.; Saavedra, M.A.; Rodriguez, J.M.; Roldan, T.; Arbelaez, C. |
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Characteristics of Emergency Medicine Residency Programs in Colombia |
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Journal Article |
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2017 |
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The Western Journal of Emergency Medicine |
Abbreviated Journal |
West J Emerg Med |
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18 |
Issue |
6 |
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1120-1127 |
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INTRODUCTION: Emergency medicine (EM) is in different stages of development around the world. Colombia has made significant strides in EM development in the last two decades and recognized it as a medical specialty in 2005. The country now has seven EM residency programs: three in the capital city of Bogota, two in Medellin, one in Manizales, and one in Cali. The seven residency programs are in different stages of maturity, with the oldest founded 20 years ago and two founded in the last two years. The objective of this study was to characterize these seven residency programs. METHODS: We conducted semi-structured interviews with faculty and residents from all the existing programs in 2013-2016. Topics included program characteristics and curricula. RESULTS: Colombian EM residencies are three-year programs, with the exception of one four-year program. Programs accept 3-10 applicants yearly. Only one program has free tuition and the rest charge tuition. The number of EM faculty ranges from 2-15. EM rotation requirements range from 11-33% of total clinical time. One program does not have a pediatric rotation. The other programs require 1-2 months of pediatrics or pediatric EM. Critical care requirements range from 4-7 months. Other common rotations include anesthesia, general surgery, internal medicine, obstetrics, gynecology, orthopedics, ophthalmology, radiology, toxicology, psychiatry, neurology, cardiology, pulmonology, and trauma. All programs offer 4-6 hours of protected didactic time each week. Some programs require Advanced Cardiac Life Support, Pediatric Advanced Life Support and Advanced Trauma Life Support, with some programs providing these trainings in-house or subsidizing the cost. Most programs require one research project for graduation. Resident evaluations consist of written tests and oral exams several times per year. Point-of-care ultrasound training is provided in four of the seven programs. CONCLUSION: As emergency medicine continues to develop in Colombia, more residency programs are expected to emerge. Faculty development and sustainability of academic pursuits will be critically important. In the long term, the specialty will need to move toward certifying board exams and professional development through a national EM organization to promote standardization across programs. |
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Harvard Affiliated Emergency Medicine Residency, Massachusetts General Hospital / Brigham and Women's Hospital, Boston, Massachusetts |
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1936-900X |
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PMID:29085546 |
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ref @ user @ |
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97625 |
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