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Yin, J.; Oh, Y.T.; Kim, J.-Y.; Kim, S.S.; Choi, E.; Kim, T.H.; Hong, J.H.; Chang, N.; Cho, H.J.; Sa, J.K.; Kim, J.C.; Kwon, H.J.; Park, S.; Lin, W.; Nakano, I.; Gwak, H.-S.; Yoo, H.; Lee, S.-H.; Lee, J.; Kim, J.H.; Kim, S.-Y.; Nam, D.-H.; Park, M.-J.; Park, J.B. |
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Title |
Transglutaminase 2 Inhibition Reverses Mesenchymal Transdifferentiation of Glioma Stem Cells by Regulating C/EBPbeta Signaling |
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Journal Article |
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Year |
2017 |
Publication |
Cancer Research |
Abbreviated Journal |
Cancer Res |
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77 |
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18 |
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4973-4984 |
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Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPbeta, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NF-kappaB activation and further degraded DNA damage-inducible transcript 3 (GADD153) to induce C/EBPbeta expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radioresistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM. Cancer Res; 77(18); 4973-84. (c)2017 AACR. |
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Specific Organs Cancer Branch, Research Institute and Hospital, National Cancer Center, Goyang, Korea |
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0008-5472 |
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PMID:28754668 |
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Call Number |
ref @ user @ |
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96575 |
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Author |
Voss, D.M.; Spina, R.; Carter, D.L.; Lim, K.S.; Jeffery, C.J.; Bar, E.E. |
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Title |
Disruption of the monocarboxylate transporter-4-basigin interaction inhibits the hypoxic response, proliferation, and tumor progression |
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Journal Article |
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Year |
2017 |
Publication |
Scientific Reports |
Abbreviated Journal |
Sci Rep |
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Volume |
7 |
Issue |
1 |
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4292 |
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We have previously shown that glioblastoma stem cells (GSCs) are enriched in the hypoxic tumor microenvironment, and that monocarboxylate transporter-4 (MCT4) is critical for mediating GSC signaling in hypoxia. Basigin is involved in many physiological functions during early stages of development and in cancer and is required for functional plasma membrane expression of MCT4. We sought to determine if disruption of the MCT-Basigin interaction may be achieved with a small molecule. Using a cell-based drug-screening assay, we identified Acriflavine (ACF), a small molecule that inhibits the binding between Basigin and MCT4. Surface plasmon resonance and cellular thermal-shift-assays confirmed ACF binding to basigin in vitro and in live glioblastoma cells, respectively. ACF significantly inhibited growth and self-renewal potential of several glioblastoma neurosphere lines in vitro, and this activity was further augmented by hypoxia. Finally, treatment of mice bearing GSC-derived xenografts resulted in significant inhibition of tumor progression in early and late-stage disease. ACF treatment inhibited intratumoral expression of VEGF and tumor vascularization. Our work serves as a proof-of-concept as it shows, for the first time, that disruption of MCT binding to their chaperon, Basigin, may be an effective approach to target GSC and to inhibit angiogenesis and tumor progression. |
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Department of Neurological Surgery, Case Western Reserve University School of Medicine and The Case Comprehensive Cancer Center, Cleveland, OH, USA. eli.bar@case.edu |
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2045-2322 |
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PMID:28655889 |
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96580 |
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Momeny, M.; Moghaddaskho, F.; Gortany, N.K.; Yousefi, H.; Sabourinejad, Z.; Zarrinrad, G.; Mirshahvaladi, S.; Eyvani, H.; Barghi, F.; Ahmadinia, L.; Ghazi-Khansari, M.; Dehpour, A.R.; Amanpour, S.; Tavangar, S.M.; Dardaei, L.; Emami, A.H.; Alimoghaddam, K.; Ghavamzadeh, A.; Ghaffari, S.H. |
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Title |
Blockade of vascular endothelial growth factor receptors by tivozanib has potential anti-tumour effects on human glioblastoma cells |
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Journal Article |
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2017 |
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Scientific Reports |
Abbreviated Journal |
Sci Rep |
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7 |
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44075 |
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Glioblastoma (GBM) remains one of the most fatal human malignancies due to its high angiogenic and infiltrative capacities. Even with optimal therapy including surgery, radiotherapy and temozolomide, it is essentially incurable. GBM is among the most neovascularised neoplasms and its malignant progression associates with striking neovascularisation, evidenced by vasoproliferation and endothelial cell hyperplasia. Targeting the pro-angiogenic pathways is therefore a promising anti-glioma strategy. Here we show that tivozanib, a pan-inhibitor of vascular endothelial growth factor (VEGF) receptors, inhibited proliferation of GBM cells through a G2/M cell cycle arrest via inhibition of polo-like kinase 1 (PLK1) signalling pathway and down-modulation of Aurora kinases A and B, cyclin B1 and CDC25C. Moreover, tivozanib decreased adhesive potential of these cells through reduction of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Tivozanib diminished GBM cell invasion through impairing the proteolytic cascade of cathepsin B/urokinase-type plasminogen activator (uPA)/matrix metalloproteinase-2 (MMP-2). Combination of tivozanib with EGFR small molecule inhibitor gefitinib synergistically increased sensitivity to gefitinib. Altogether, these findings suggest that VEGFR blockade by tivozanib has potential anti-glioma effects in vitro. Further in vivo studies are warranted to explore the anti-tumour activity of tivozanib in combinatorial approaches in GBM. |
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Haematology/Oncology and Stem Cell Transplantation Research Centre, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran |
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2045-2322 |
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PMID:28287096 |
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ref @ user @ |
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96601 |
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Howard, C.M.; Valluri, J.; Alberico, A.; Julien, T.; Mazagri, R.; Marsh, R.; Alastair, H.; Cortese, A.; Griswold, M.; Wang, W.; Denning, K.; Brown, L.; Claudio, P.P. |
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Title |
Analysis of Chemopredictive Assay for Targeting Cancer Stem Cells in Glioblastoma Patients |
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Journal Article |
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Year |
2017 |
Publication |
Translational Oncology |
Abbreviated Journal |
Transl Oncol |
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10 |
Issue |
2 |
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241-254 |
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INTRODUCTION: The prognosis of glioblastoma (GBM) treated with standard-of-care maximal surgical resection and concurrent adjuvant temozolomide (TMZ)/radiotherapy remains very poor (less than 15 months). GBMs have been found to contain a small population of cancer stem cells (CSCs) that contribute to tumor propagation, maintenance, and treatment resistance. The highly invasive nature of high-grade gliomas and their inherent resistance to therapy lead to very high rates of recurrence. For these reasons, not all patients with similar diagnoses respond to the same chemotherapy, schedule, or dose. Administration of ineffective anticancer therapy is not only costly but more importantly burdens the patient with unnecessary toxicity and selects for the development of resistant cancer cell clones. We have developed a drug response assay (ChemoID) that identifies the most effective chemotherapy against CSCs and bulk of tumor cells from of a panel of potential treatments, offering great promise for individualized cancer management. Providing the treating physician with drug response information on a panel of approved drugs will aid in personalized therapy selections of the most effective chemotherapy for individual patients, thereby improving outcomes. A prospective study was conducted evaluating the use of the ChemoID drug response assay in GBM patients treated with standard of care. METHODS: Forty-one GBM patients (mean age 54 years, 59% male), all eligible for a surgical biopsy, were enrolled in an Institutional Review Board-approved protocol, and fresh tissue samples were collected for drug sensitivity testing. Patients were all treated with standard-of-care TMZ plus radiation with or without maximal surgery, depending on the status of the disease. Patients were prospectively monitored for tumor response, time to recurrence, progression-free survival (PFS), and overall survival (OS). Odds ratio (OR) associations of 12-month recurrence, PFS, and OS outcomes were estimated for CSC, bulk tumor, and combined assay responses for the standard-of-care TMZ treatment; sensitivities/specificities, areas under the curve (AUCs), and risk reclassification components were examined. RESULTS: Median follow-up was 8 months (range 3-49 months). For every 5% increase in in vitro CSC cell kill by TMZ, 12-month patient response (nonrecurrence of cancer) increased two-fold, OR=2.2 (P=.016). Similar but somewhat less supported associations with the bulk tumor test were seen, OR=2.75 (P=.07) for each 5% bulk tumor cell kill by TMZ. Combining CSC and bulk tumor assay results in a single model yielded a statistically supported CSC association, OR=2.36 (P=.036), but a much attenuated remaining bulk tumor association, OR=1.46 (P=.472). AUCs and [sensitivity/specificity] at optimal outpoints (>40% CSC cell kill and >55% bulk tumor cell kill) were AUC=0.989 [sensitivity=100/specificity=97], 0.972 [100/89], and 0.989 [100/97] for the CSC only, bulk tumor only, and combined models, respectively. Risk categorization of patients was improved by 11% when using the CSC test in conjunction with the bulk test (risk reclassification nonevent net reclassification improvement [NRI] and overall NRI=0.111, P=.030). Median recurrence time was 20 months for patients with a positive (>40% cell kill) CSC test versus only 3 months for those with a negative CSC test, whereas median recurrence time was 13 months versus 4 months for patients with a positive (>55% cell kill) bulk test versus negative. Similar favorable results for the CSC test were observed for PFS and OS outcomes. Panel results across 14 potential other treatments indicated that 34/41 (83%) potentially more optimal alternative therapies may have been chosen using CSC results, whereas 27/41 (66%) alternative therapies may have been chosen using bulk tumor results. CONCLUSIONS: The ChemoID CSC drug response assay has the potential to increase the accuracy of bulk tumor assays to help guide individualized chemotherapy choices. GBM cancer recurrence may occur quickly if the CSC test has a low in vitro cell kill rate even if the bulk tumor test cell kill rate is high. |
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Department of BioMolecular Sciences, National Center for Natural Products Research, University of Mississippi, University, MS; Department of Radiation Oncology, University of Mississippi Medical Center Cancer Institute, Jackson, MS 39216. Electronic address: pclaudio@olemiss.edu |
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1936-5233 |
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PMID:28199863 |
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Call Number |
ref @ user @ |
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96608 |
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Sacks, E.; Freeman, P.A.; Sakyi, K.; Jennings, M.C.; Rassekh, B.M.; Gupta, S.; Perry, H.B. |
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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 |
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Journal Article |
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Year |
2017 |
Publication |
Journal of Global Health |
Abbreviated Journal |
J Glob Health |
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7 |
Issue |
1 |
Pages |
010903 |
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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. |
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Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA |
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2047-2978 |
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PMID:28685041 |
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ref @ user @ |
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97042 |
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