| Records |
| Author |
Jin, W.-L.; Mao, X.-Y.; Qiu, G.-Z. |
| Title |
Targeting Deubiquitinating Enzymes in Glioblastoma Multiforme: Expectations and Challenges |
Type |
Journal Article |
| Year |
2017 |
Publication |
Medicinal Research Reviews |
Abbreviated Journal |
Med Res Rev |
| Volume |
37 |
Issue |
3 |
Pages |
627-661 |
| Keywords |
Animals; Carcinogenesis/pathology; Deubiquitinating Enzymes/antagonists & inhibitors/*metabolism; Enzyme Inhibitors/pharmacology; Glioblastoma/*enzymology/*therapy; Humans; *Molecular Targeted Therapy; Neoplastic Stem Cells/drug effects/pathology; DUB inhibitor; DUBs; glioblastoma; glioma stem cells; proteasome |
| Abstract |
Glioblastoma (GBM) is regarded as the most common primary intracranial neoplasm. Despite standard treatment with tumor resection and radiochemotherapy, the outcome remains gloomy. It is evident that a combination of oncogenic gain of function and tumor-suppressive loss of function has been attributed to glioma initiation and progression. The ubiquitin-proteasome system is a well-orchestrated system that controls the fate of most proteins by striking a dynamic balance between ubiquitination and deubiquitination of substrates, having a profound influence on the modulation of oncoproteins, tumor suppressors, and cellular signaling pathways. In recent years, deubiquitinating enzymes (DUBs) have emerged as potential anti-cancer targets due to their targeting several key proteins involved in the regulation of tumorigenesis, apoptosis, senescence, and autophagy. This review attempts to summarize recent studies of GBM-associated DUBs, their roles in various cellular processes, and discuss the relation between DUBs deregulation and gliomagenesis, especially how DUBs regulate glioma stem cells pluripotency, microenvironment, and resistance of radiation and chemotherapy through core stem-cell transcriptional factors. We also review recent achievements and progress in the development of potent and selective reversible inhibitors of DUBs, and attempted to find a potential GBM treatment by DUBs intervention. |
| Address |
Department of Neurosurgery, General Hospital of Jinan Military Command, Jinan, 250031, P. R. China |
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English |
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| ISSN |
0198-6325 |
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| Notes |
PMID:27775833 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial |
96629 |
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| Author |
Nourallah, B.; Digpal, R.; Jena, R.; Watts, C. |
| Title |
Irradiating the Subventricular Zone in Glioblastoma Patients: Is there a Case for a Clinical Trial? |
Type |
Journal Article |
| Year |
2017 |
Publication |
Clinical Oncology (Royal College of Radiologists (Great Britain)) |
Abbreviated Journal |
Clin Oncol (R Coll Radiol) |
| Volume |
29 |
Issue |
1 |
Pages |
26-33 |
| Keywords |
Adult; Brain Neoplasms/*radiotherapy; Glioblastoma/*radiotherapy; Humans; Lateral Ventricles/*radiation effects; Male; Neoplastic Stem Cells/radiation effects; Stem Cell Niche/radiation effects; Cancer stem cells; glioblastoma; neural stem cells; radiotherapy; subventricular zone |
| Abstract |
Glioblastoma is the most common and aggressive adult brain tumour. Over the last 10 years it has emerged that the subventricular zone (SVZ), the largest adult neural stem cell niche, has an important role in the disease. Converging evidence has implicated transformation of adult neural stems in gliomagenesis and the permissive stem cell niche in disease recurrence. Concurrently, clinical studies have suggested that SVZ involvement is a negative prognostic marker. It would follow that irradiating the SVZ may improve outcomes in glioblastoma by directly targeting this putative sanctuary site. To investigate this potential strategy, 11 retrospective studies and 1 prospective study examined the relationship between dose to the SVZ and survival outcomes in glioblastoma patients. This review summarises the theoretical underpinning of this strategy, provides a critical evaluation of the existing evidence and discusses the rationale for a clinical trial. |
| Address |
John van Geest Centre for Repair, Cambridge, UK; Department of Clinical Neurosciences, Division of Neurosurgery, Addenbrookes Hospital, Cambridge, UK. Electronic address: cw209@cam.ac.uk |
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English |
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0936-6555 |
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| Notes |
PMID:27729188 |
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no |
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ref @ user @ |
Serial |
96633 |
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Luedi, M.M.; Singh, S.K.; Mosley, J.C.; Hatami, M.; Gumin, J.; Sulman, E.P.; Lang, F.F.; Stueber, F.; Zinn, P.O.; Colen, R.R. |
| Title |
A Dexamethasone-regulated Gene Signature Is Prognostic for Poor Survival in Glioblastoma Patients |
Type |
Journal Article |
| Year |
2017 |
Publication |
Journal of Neurosurgical Anesthesiology |
Abbreviated Journal |
J Neurosurg Anesthesiol |
| Volume |
29 |
Issue |
1 |
Pages |
46-58 |
| Keywords |
Animals; Antineoplastic Agents, Hormonal/*pharmacology; Apoptosis; Blotting, Western; Brain Neoplasms/*mortality; Cell Line, Tumor; Cell Survival; Dexamethasone/*pharmacology; Flow Cytometry; Gene Expression Regulation, Neoplastic/*drug effects; Glioblastoma/*mortality; Humans; Mice; Prognosis; Stem Cells/drug effects; Survival Analysis |
| Abstract |
BACKGROUND: Dexamethasone is reported to induce both tumor-suppressive and tumor-promoting effects. The purpose of this study was to identify the genomic impact of dexamethasone in glioblastoma stem cell (GSC) lines and its prognostic value; furthermore, to identify drugs that can counter these side effects of dexamethasone exposure. METHODS: We utilized 3 independent GSC lines with tumorigenic potential for this study. Whole-genome expression profiling and pathway analyses were done with dexamethasone-exposed and control cells. GSCs were also co-exposed to dexamethasone and temozolomide. Risk scores were calculated for most affected genes, and their associations with survival in The Cancer Genome Atlas and Repository of Molecular Brain Neoplasia Data databases. In silico Connectivity Map analysis identified camptothecin as antagonist to dexamethasone-induced negative effects. RESULTS: Pathway analyses predicted an activation of dexamethasone network (z-score: 2.908). Top activated canonical pathways included “role of breast cancer 1 in DNA damage response” (P=1.07E-04). GSCs were protected against temozolomide-induced apoptosis when coincubated with dexamethasone. Altered cellular functions included cell movement, cell survival, and apoptosis with z-scores of 2.815, 5.137, and -3.122, respectively. CCAAT/enhancer binding protein beta (CEBPB) was activated in a dose dependent manner specifically in slow-dividing “stem-like” cells. CEBPB was activated in dexamethasone-treated orthotopic tumors. Patients with high risk scores had significantly shorter survival. Camptothecin was validated as potential partial neutralizer of dexamethasone-induced oncogenic effects. CONCLUSIONS: Dexamethasone exposure induces a genetic program and CEBPB expression in GSCs that adversely affects key cellular functions and response to therapeutics. High risk scores associated with these genes have negative prognostic value in patients. Our findings further suggest camptothecin as a potential neutralizer of adverse dexamethasone-mediated effects. |
| Address |
*Department of Anesthesiology, Bern University Hospital Inselspital, Bern, Switzerland Departments of daggerCancer Systems Imaging double daggerDiagnostic Imaging section signNeurosurgery and Brain Tumor Center parallelRadiation Oncology, Division of Radiation Oncology #Neurosurgery, Cancer Systems Imaging, and Cancer Biology **Cancer Systems Imaging, and Diagnostic Imaging, The University of Texas MD Anderson Cancer Center paragraph signDepartment of Neurosurgery, Baylor College of Medicine, Houston, TX |
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English |
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0898-4921 |
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| Notes |
PMID:27653222 |
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no |
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ref @ user @ |
Serial |
96635 |
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Goffart, N.; Lombard, A.; Lallemand, F.; Kroonen, J.; Nassen, J.; Di Valentin, E.; Berendsen, S.; Dedobbeleer, M.; Willems, E.; Robe, P.; Bours, V.; Martin, D.; Martinive, P.; Maquet, P.; Rogister, B. |
| Title |
CXCL12 mediates glioblastoma resistance to radiotherapy in the subventricular zone |
Type |
Journal Article |
| Year |
2017 |
Publication |
Neuro-Oncology |
Abbreviated Journal |
Neuro Oncol |
| Volume |
19 |
Issue |
1 |
Pages |
66-77 |
| Keywords |
Animals; Brain Neoplasms/metabolism/*pathology/radiotherapy; Chemokine CXCL12/*metabolism; Cranial Irradiation/*adverse effects; Gamma Rays/adverse effects; Glioblastoma/metabolism/*pathology/radiotherapy; Humans; Lateral Ventricles/metabolism/*pathology/radiation effects; Mice; Mice, Nude; Neoplastic Stem Cells/metabolism/*pathology/radiation effects; *Radiation Tolerance; Signal Transduction/radiation effects; Tumor Cells, Cultured; Cxcl12; glioblastoma; mesenchymal activation; radioresistance; subventricular zone |
| Abstract |
BACKGROUND: Patients with glioblastoma (GBM) have an overall median survival of 15 months despite multimodal therapy. These catastrophic survival rates are to be correlated to systematic relapses that might arise from remaining glioblastoma stem cells (GSCs) left behind after surgery. In this line, it has recently been demonstrated that GSCs are able to escape the tumor mass and preferentially colonize the adult subventricular zone (SVZ). At a distance from the initial tumor site, these GSCs might therefore represent a high-quality model of clinical resilience to therapy and cancer relapses as they specifically retain tumor-initiating abilities. METHOD: While relying on recent findings that have validated the existence of GSCs in the human SVZ, we questioned the role of the SVZ niche as a potential GSC reservoir involved in therapeutic failure. RESULTS: Our results demonstrate that (i) GSCs located in the SVZ are specifically resistant to radiation in vivo, (ii) these cells display enhanced mesenchymal roots that are known to be associated with cancer radioresistance, (iii) these mesenchymal traits are specifically upregulated by CXCL12 (stromal cell-derived factor-1) both in vitro and in the SVZ environment, (iv) the amount of SVZ-released CXCL12 mediates GBM resistance to radiation in vitro, and (v) interferes with the CXCL12/CXCR4 signalling system, allowing weakening of the tumor mesenchymal roots and radiosensitizing SVZ-nested GBM cells. CONCLUSION: Together, these data provide evidence on how the adult SVZ environment, through the release of CXCL12, supports GBM therapeutic failure and potential tumor relapse. |
| Address |
Laboratory of Developmental Neurobiology, GIGA-Neurosciences Research Center, University of Liege, Liege, Belgium (N.G., A.L., J.N., M.D., E.W., B.R.); Department of Neurosurgery, CHU and University of Liege, Liege, Belgium (A.L., D.M.); Department of Radiotherapy and Oncology, CHU and University of Liege, Liege, Belgium (F.L., P.M.); Laboratory of Tumor and Development Biology, GIGA-Cancer Research Center, University of Liege, Liege, Belgium (F.L.); Cyclotron Research Centre, University of Liege, Liege, Belgium (F.L.); Human Genetics, CHU and University of Liege, Liege, Belgium (N.G., J.K., V.B.); Department of Neurosurgery, Brain Center Rudolf Magnus Institute of Neurosciences and the T&P Bohnenn Laboratory for Neuro-Oncology University Medical Center, Utrecht, The Netherlands (N.G., J.K., S.B., P.R.); GIGA-Viral Vector Plateform, University of Liege, Liege, Belgium (E.D.V.); Department of Neurology, CHU and University of Liege, Liege, Belgium (P.M., B.R.) |
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1522-8517 |
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| Notes |
PMID:27370398 |
Approved |
no |
| Call Number |
ref @ user @ |
Serial |
96647 |
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Sacks, E.; Freeman, P.A.; Sakyi, K.; Jennings, M.C.; Rassekh, B.M.; Gupta, S.; Perry, H.B. |
| Title |
Comprehensive review of the evidence regarding the effectiveness of community-based primary health care in improving maternal, neonatal and child health: 3. neonatal health findings |
Type |
Journal Article |
| Year |
2017 |
Publication |
Journal of Global Health |
Abbreviated Journal |
J Glob Health |
| Volume |
7 |
Issue |
1 |
Pages |
010903 |
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| Abstract |
BACKGROUND: As the number of deaths among children younger than 5 years of age continues to decline globally through programs to address the health of older infants, neonatal mortality is becoming an increasingly large proportion of under-5 deaths. Lack of access to safe delivery care, emergency obstetric care and postnatal care continue to be challenges for reducing neonatal mortality. This article reviews the available evidence regarding the effectiveness of community-based primary health care (CBPHC) and common components of programs aiming to improve health during the first 28 days of life. METHODS: A database comprising evidence of the effectiveness of projects, programs and field research studies (referred to collectively as projects) in improving maternal, neonatal and child health through CBPHC has been assembled and described elsewhere in this series. From this larger database (N = 548), a subset was created from assessments specifically relating to newborn health (N = 93). Assessments were excluded if the primary project beneficiaries were more than 28 days of age, or if the assessment did not identify one of the following outcomes related to neonatal health: changes in knowledge about newborn illness, care seeking for newborn illness, utilization of postnatal care, nutritional status of neonates, neonatal morbidity, or neonatal mortality. Descriptive analyses were conducted based on study type and outcome variables. An equity assessment was also conducted on the articles included in the neonatal subset. RESULTS: There is strong evidence that CBPHC can be effective in improving neonatal health, and we present information about the common characteristics shared by effective programs. For projects that reported on health outcomes, twice as many reported an improvement in neonatal health as did those that reported no effect; only one study demonstrated a negative effect. Of those with the strongest experimental study design, almost three-quarters reported beneficial neonatal health outcomes. Many of the neonatal projects assessed in our database utilized community health workers (CHWs), home visits, and participatory women's groups. Several of the interventions used in these projects focused on health education (recognition of danger signs), and promotion of and support for exclusive breastfeeding (sometimes, but not always, including early breastfeeding). Almost all of the assessments that included a measurable equity component showed that CBPHC produced neonatal health benefits that favored the poorest segment of the project population. However, the studies were quite biased in geographic scope, with more than half conducted in South Asia, and many were pilot studies, rather than projects at scale. CONCLUSIONS: CBPHC can be effectively employed to improve neonatal health in high-mortality, resource-constrained settings. CBPHC is especially important for education and support for pregnant and postpartum mothers and for establishing community-facility linkages to facilitate referrals for obstetrical emergencies; however, the latter will only produce better health outcomes if facilities offer timely, high-quality care. Further research on this topic is needed in Africa and Latin America, as well as in urban and peri-urban areas. Additionally, more assessments are needed of integrated packages of neonatal interventions and of programs at scale. |
| Address |
Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA |
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English |
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2047-2978 |
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| Notes |
PMID:28685041 |
Approved |
no |
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ref @ user @ |
Serial |
97042 |
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