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G G, Bharti S, Jha VC, Nigam JS, Ganesh R A, Bhadani P. Immunoexpression of Survivin and P53 in the Histological Subtypes of Medulloblastoma: A Cross-Sectional Observational Study. Cureus 2024; 16:e65627. [PMID: 39205763 PMCID: PMC11350522 DOI: 10.7759/cureus.65627] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/29/2024] [Indexed: 09/04/2024] Open
Abstract
Medulloblastoma (MB) is a common malignant intracranial neoplasms in children. The treatment and prognosis of this tumor depends on histology and molecular subtypes. Survivin, implicated in various malignancies, may hold prognostic significance. We investigated survivin and p53 immunoreactivity in different histological subtypes in 20 MB cases from January 2018 to June 2021. Immunohistochemistry revealed survivin expression in 75% (15/20) of cases, with cytoplasmic (10 cases), nuclear (four cases), or combined expression (one case). p53 nuclear expression was present in 35% (7/20) of cases. Classical variant MB exhibited predominant p53 and cytoplasmic survivin expression. Given the association of survivin and p53 expression with poor prognosis, especially in the prevalent classical variant, targeted therapies may hold promise for MB treatment advancement.
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Affiliation(s)
- Guralarasan G
- Pathology and Lab Medicine, All India Institute of Medical Sciences, Patna, Patna, IND
| | - Shreekant Bharti
- Pathology and Lab Medicine, All India Institute of Medical Sciences, Patna, Patna, IND
| | - Vikas C Jha
- Neurosurgery, All India Institute of Medical Sciences, Patna, Patna, IND
| | - Jitendra S Nigam
- Pathology and Lab Medicine, All India Institute of Medical Sciences, Bibinagar, Bibinagar, IND
| | - Abhirami Ganesh R
- Pathology and Lab Medicine, All India Institute of Medical Sciences, Patna, Patna, IND
| | - Punam Bhadani
- Pathology and Lab Medicine, All India Institute of Medical Sciences, Patna, Patna, IND
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Wild type, dEX3 and 2B survivin isoforms localize to the tumor cell plasma membrane, are secreted in exosomes, and interact with extracellular tubulin. Biochem Biophys Rep 2021; 28:101174. [PMID: 34849411 PMCID: PMC8608592 DOI: 10.1016/j.bbrep.2021.101174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/11/2021] [Accepted: 11/13/2021] [Indexed: 11/20/2022] Open
Abstract
The Inhibitor of Apoptosis Protein survivin (svn) is upregulated in nearly all types of cancer and represents a promising therapeutic target. Localization to specific subcellular compartments and interactions with various binding partners allow survivin to play diverse roles in apoptosis resistance and mitosis. Survivin has recently been found in two extracellular compartments: the outer plasma membrane and secreted exosomes. In addition to svn-wt, splice variants svn-dEX3 and svn-2B are also overexpressed in human tumors. Here we show that, similarly to svn-wt, svn-dEX3 and svn-2B can be displayed on the outer plasma membrane, and secreted in exosomes. Additionally, we have identified a novel interaction of all three forms of survivin with secreted tubulin.
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Ma J, Tian K, Du J, Wu Z, Wang L, Zhang J. High expression of survivin independently correlates with tumor progression and mortality in patients with skull base chordomas. J Neurosurg 2020; 132:140-149. [PMID: 30641849 DOI: 10.3171/2018.8.jns181580] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 08/14/2018] [Indexed: 11/06/2022]
Abstract
OBJECTIVE The object of this study was to clarify the expression characteristics and prognostic value of survivin in skull base chordomas. METHODS In this retrospective study, the authors measured the expression of survivin at the mRNA level in 81 samples from 71 patients diagnosed with skull base chordomas at their hospital in the period from July 2005 to January 2015. Clinical data collection, follow-up, and survival analyses were performed, and correlations were analyzed. RESULTS Of the 71 patients, 50 had primary chordomas with a mean survivin expression level of 1.09; the other 21 patients had recurrent chordomas with a mean survivin expression level of 2.57, which was 2.36 times higher than the level in the primary chordoma patients (p < 0.001, Mann-Whitney U-test). In addition, an analysis of 18 paired samples derived from 9 patients showed that the expression level of survivin was 2.62 times higher in recurrent tumors than in primary tumors (p = 0.002, paired t-test). The Spearman rank correlation coefficient method showed that the expression level of survivin was positively correlated with the mean ratio of tumor signal intensity to the signal intensity of surrounding brainstem on T1-weighted sequences (RT1; rs = 0.274, p = 0.021) and was negatively correlated with the mean ratio of tumor signal intensity to the signal intensity of surrounding brainstem on T2-weighted sequences (RT2; rs = -0.389, p = 0.001). A multivariate Cox proportional-hazards model suggested that pathology (p = 0.041), survivin expression level (p = 0.018), preoperative Karnofsky Performance Status (KPS; p = 0.012), and treatment history (p = 0.009) were independent prognostic factors for tumor progression. Survivin expression level (p = 0.008), preoperative KPS (p = 0.019), tumor diameter (p = 0.027), and intraoperative blood loss (p = 0.015) were independent prognostic factors for death. CONCLUSIONS Survivin expression level and preoperative KPS were independent significant prognostic factors for tumor progression and death in skull base chordoma patients. Recurrent skull base chordomas and chordomas with high RT1 and low RT2 were likely to have high survivin expression. Other independent risk factors related to tumor progression included conventional pathology and treatment history, whereas additional mortality-related risk factors included larger tumor diameter and greater intraoperative blood loss.
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Affiliation(s)
- Junpeng Ma
- 1Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University
- 3China National Clinical Research Center for Neurological Diseases, Beijing, People's Republic of China
| | - Kaibing Tian
- 1Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University
- 3China National Clinical Research Center for Neurological Diseases, Beijing, People's Republic of China
| | - Jiang Du
- 2Department of Neuropathology, Beijing Neurosurgical Institute, Capital Medical University; and
- 3China National Clinical Research Center for Neurological Diseases, Beijing, People's Republic of China
| | - Zhen Wu
- 1Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University
- 3China National Clinical Research Center for Neurological Diseases, Beijing, People's Republic of China
| | - Liang Wang
- 1Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University
- 3China National Clinical Research Center for Neurological Diseases, Beijing, People's Republic of China
| | - Junting Zhang
- 1Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University
- 3China National Clinical Research Center for Neurological Diseases, Beijing, People's Republic of China
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Topyalin N, Budak M, Ozbay N, Yildiz M, Kaner T, Aydin A, Gezen AF. A comparative histopathological and immunohistochemical study of Survivin and Ki-67 proteins in glial tumours. BIOTECHNOL BIOTEC EQ 2019. [DOI: 10.1080/13102818.2019.1591931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022] Open
Affiliation(s)
- Nur Topyalin
- Neurosurgery Clinic, Istanbul Medeniyet University, Goztepe Training and Research Hospital, Istanbul, Turkey
| | - Metin Budak
- Faculty of Medicine, Department of Biophysics, Trakya University, Edirne, Turkey
| | - Nurver Ozbay
- Department of Pathology, Istanbul Medeniyet University, Goztepe Training and Research Hospital, Istanbul, Turkey
| | - Mustafa Yildiz
- Faculty of Medicine, Department of Biophysics, Trakya University, Edirne, Turkey
| | - Tuncay Kaner
- Neurosurgery Clinic, Istanbul Medeniyet University, Goztepe Training and Research Hospital, Istanbul, Turkey
| | - Abdullah Aydin
- Neurosurgery Clinic, Istanbul Medeniyet University, Goztepe Training and Research Hospital, Istanbul, Turkey
| | - Ahmet Ferruh Gezen
- Neurosurgery Clinic, Istanbul Medeniyet University, Goztepe Training and Research Hospital, Istanbul, Turkey
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5
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Faccion RS, Bernardo PS, de Lopes GPF, Bastos LS, Teixeira CL, de Oliveira JA, Fernandes PV, Dubois LG, Chimelli L, Maia RC. p53 expression and subcellular survivin localization improve the diagnosis and prognosis of patients with diffuse astrocytic tumors. Cell Oncol (Dordr) 2018; 41:141-157. [DOI: 10.1007/s13402-017-0361-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/07/2017] [Indexed: 12/12/2022] Open
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Emamzadeh FN. Role of Apolipoproteins and α-Synuclein in Parkinson's Disease. J Mol Neurosci 2017; 62:344-355. [PMID: 28695482 PMCID: PMC5541107 DOI: 10.1007/s12031-017-0942-9] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 06/12/2017] [Indexed: 12/25/2022]
Abstract
Parkinson's disease (PD) is a progressive brain disorder that interferes with activities of normal life. The main pathological feature of this disease is the loss of more than 80% of dopamine-producing neurons in the substantia nigra (SN). Dopaminergic neuronal cell death occurs when intraneuronal, insoluble, aggregated proteins start to form Lewy bodies (LBs), the most important component of which is a protein called α-synuclein (α-syn). α-Syn structurally contains hexameric repeats of 11 amino acids, which are characteristic of apolipoproteins and thus α-syn can also be considered an apolipoprotein. Moreover, apolipoproteins seem to be involved in the incidence and development of PD. Some apolipoproteins such as ApoD have a neuroprotective role in the brain. In PD, apoD levels increase in glial cells surrounding dopaminergic cells. However, elevated levels of some other apolipoproteins such as ApaA1 and ApoE are reported as a vulnerability factor of PD. At present, when a clinical diagnosis of PD is made, based on symptoms such as shaking, stiff muscles and slow movement, serious damage has already been done to nerve cells of the SN. The diagnosis of PD in its earlier stages, before this irreversible damage, would be of enormous benefit for future treatment strategies designed to slow or halt the progression of PD. This review presents the roles of apolipoproteins and α-syn in PD and how some of them could potentially be used as biomarkers for PD.
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Affiliation(s)
- Fatemeh Nouri Emamzadeh
- Division of Biomedical and Life Sciences, Faculty of Health and Medicine, University of Lancaster, Lancaster, LA1 4AY, UK.
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Bae IS, Kim CH, Kim JM, Cheong JH, Ryu JI, Han MH. Correlation of survivin and B-cell lymphoma 2 expression with pathological malignancy and anti-apoptotic properties of glial cell tumors. Biomed Rep 2017; 6:396-400. [PMID: 28413637 DOI: 10.3892/br.2017.861] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 01/27/2017] [Indexed: 01/17/2023] Open
Abstract
Apoptosis, whose mechanism remains unclear, is regulated by multiple factors. B-cell lymphoma 2 (Bcl-2) is a well-known anti-apoptotic mediator. Survivin is also a recently recognized novel family inhibitor of apoptosis protein, which inhibits apoptosis via a pathway distinct from Bcl-2 family members. Survivin and Bcl-2 are expressed in various types of human cancer. In the present study, survivin and Bcl-2 expression were characterized in glial cell tumors, and the correlation with pathological malignancy and anti-apoptotic properties were investigated. Fifty-eight patients who had undergone surgical resection for glial cell tumors were evaluated. The pathological types of glial cell tumors were categorized according to the World Health Organization classification. Survivin and Bcl-2 expression levels were investigated by western blot analysis, and apoptosis was detected by DNA fragmentation analysis. The anti-apoptotic rate of glial cell tumors was calculated in tumor samples according to the expression of survivin and Bcl-2 or co-expression. Survivin was characterized in 60.3%, and Bcl-2 was expressed in 43.1% of glioma samples. Co-expression of survivin and Bcl-2 was observed in 25.9% of the tumor specimens. Survivin expression in astrocytic tumors was identified to be significantly associated with the pathological grade (P<0.05); however, Bcl-2 was not (P>0.05). Anti-apoptotic rate of glial cell tumors were detected in 91.4, 92.0 and 100% of patients exhibiting survivin, Bcl-2 or co-expression, respectively. However, the difference in anti-apoptotic frequency between the three groups was not identified to be statistically significant (P>0.05). The present study suggests that survivin expression is correlated with pathological grades of gliomas. In addition, the expression of survivin or Bcl-2 exerts potent anti-apoptotic properties in gliomas. Thus, survivin or Bcl-2 may serve as potential targets for inducing the apoptosis of gliomas.
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Affiliation(s)
- In-Suk Bae
- Department of Neurosurgery, Hanyang University Guri Hospital, Guri-si, Gyeonggi-do 11923, Republic of Korea
| | - Choong-Hyun Kim
- Department of Neurosurgery, Hanyang University Guri Hospital, Guri-si, Gyeonggi-do 11923, Republic of Korea
| | - Jae-Min Kim
- Department of Neurosurgery, Hanyang University Guri Hospital, Guri-si, Gyeonggi-do 11923, Republic of Korea
| | - Jin-Hwan Cheong
- Department of Neurosurgery, Hanyang University Guri Hospital, Guri-si, Gyeonggi-do 11923, Republic of Korea
| | - Je-Il Ryu
- Department of Neurosurgery, Hanyang University Guri Hospital, Guri-si, Gyeonggi-do 11923, Republic of Korea
| | - Myung-Hoon Han
- Department of Neurosurgery, Hanyang University Guri Hospital, Guri-si, Gyeonggi-do 11923, Republic of Korea
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Shehata HH, Abou Ghalia AH, Elsayed EK, Ahmed Said AM, Mahmoud SS. Clinical significance of high levels of survivin and transforming growth factor beta-1 proteins in aqueous humor and serum of retinoblastoma patients. J AAPOS 2016; 20:444.e1-444.e9. [PMID: 27663628 DOI: 10.1016/j.jaapos.2016.07.223] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Revised: 07/11/2016] [Accepted: 07/17/2016] [Indexed: 12/30/2022]
Abstract
PURPOSE To evaluate the diagnostic and prognostic values of survivin and transforming growth factor beta-1 (TGF-B1) expression in aqueous humor and serum of retinoblastoma (RB) in comparison to the conventional RB marker lactate dehydrogenase (LDH) and to elucidate a possible correlation between them and the clinicopathological features of the disease. METHODS This prospective, comparative study included 88 newly diagnosed children with RB and 80 age-matched controls with ophthalmic conditions other than tumors prepared for intraocular surgeries. Concentrations of survivin, TGF-B1, and LDH were measured in serum and aqueous humor before and 6 months after completion of therapy. RESULTS High serum and aqueous humor concentrations of the three proteins were detected in RB patients before treatment compared to the control group (P < 0.01), with a significant reduction of serum concentrations after treatment (P < 0.01). For the highest sensitivity and specificity, the optimal cutoff values of serum and aqueous survivin were 12.9 pg/ml and 25.2 pg/mg, with a significant positive correlation between aqueous survivin and RB staging and presence of optic nerve infiltration (r = 0.43, P = 0.04); the best cutoff values of serum and aqueous TGF-B1, 370.7 pg/ml and 39.8 pg/mg, with a significant positive correlation between aqueous TGF-B1 and poor differentiation of the tumor (r = 0.69, P = 0.001). CONCLUSIONS The high sensitivity, specificity, and accuracy of serum and aqueous humor survivin and TGF-B1 proteins make them promising markers for early detection and follow-up of RB patients.
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Affiliation(s)
- Hanan Hussein Shehata
- Medical Biochemistry Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | | | - Eman Khairy Elsayed
- Medical Biochemistry Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | | | - Safaa Saleh Mahmoud
- Ophthalmology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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9
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Survivin, caspase-3 and MIB-1 expression in astrocytic tumors of various grades. Adv Med Sci 2016; 61:237-243. [PMID: 26995334 DOI: 10.1016/j.advms.2016.02.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Revised: 01/22/2016] [Accepted: 02/02/2016] [Indexed: 02/08/2023]
Abstract
PURPOSE Gliomas are the most common primary brain tumors. The etiology is still unclear and the progression from low to high-grade gliomas is frequent. The molecular mechanisms are quite established, however the heterogeneity of glioblastomas force the scientist to look for the new therapeutic targets. The aim of the study was to evaluate the caspase-3 and survivin expression in correlation with MIB-1 expression in gliomas of various grade to assess the apoptosis in gliomas and to determinate new possible targets for the future therapy. MATERIAL AND METHODS We identified 131 patients with a histopathological diagnosis of astrocytic tumors (diffuse astrocytoma, anaplastic astrocytoma and glioblastoma). The evaluation of caspase-3, survivin and MIB-1 expression was done using immunohistochemical methods. RESULTS Caspase-3 and survivin expression was observed both in low- and high-grade astrocytomas. The differences in expression were the most evident in glioblastoma group. All primary glioblastomas (31 cases) expressed caspase-3. In secondary glioblastoma group only 17 out of 30 specimens were positive for caspase-3. Survivin expression was observed in 80.6% primary glioblastomas and in all examined secondary glioblastomas and the staining was strong and diffuse in all cases. MIB-1 expression was low in diffuse astrocytomas (DA) and ranged between 1 and 5%. In anaplastic astrocytoma group it was ranged between 5 and 10% and the highest percentage of the positive cells was observed in glioblastoma cases and ranged from 10% even to 30%. The most evident MIB-1 expression was observed in the cells surrounding the pathological blood vessels and necrosis. CONCLUSIONS The high incidence of survivin and caspase-3 expression in diffuse and anaplastic astrocytoma cases may suggest, that the regulation between pro- and antiapoptotic proteins may play an important role in tumor growth and progression. The overexpression of survivin and MIB-1 expression in glioblastoma cases also may confirm the theory about the important role of anti-apoptotic and proliferation processes in glioblastoma progression and as such may be potential therapeutic targets.
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Lee SH, Lee EH, Lee SH, Lee YM, Kim HD, Kim YZ. Epigenetic Role of Histone 3 Lysine Methyltransferase and Demethylase in Regulating Apoptosis Predicting the Recurrence of Atypical Meningioma. J Korean Med Sci 2015; 30:1157-66. [PMID: 26240495 PMCID: PMC4520948 DOI: 10.3346/jkms.2015.30.8.1157] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Accepted: 04/07/2015] [Indexed: 12/27/2022] Open
Abstract
Alteration of apoptosis is related with progression and recurrence of atypical meningiomas (AMs). However, no comprehensive study has been conducted regarding histone modification regulating apoptosis in AMs. This study aimed to determine the prognostic values of certain apoptosis-associated factors, and examine the role of histone modification on apoptosis in AMs. The medical records of 67 patients with AMs, as diagnosed during recent 13 yr, were reviewed retrospectively. Immunohistochemical staining was performed on archived paraffin-embedded tissues for pro-apoptotic factors (CASP3, IGFBP, TRAIL-R1, BAX, and XAF1), anti-apoptotic factors (survivin, ERK, RAF1, MDM2, and BCL2), and the histone modifying enzymes (MLL2, RIZ, EZH1, NSD2, KDM5c, JMJD2a, UTX, and JMJD5). Twenty-six (38.8%) patients recurred during the follow-up period (mean duration 47.7 months). In terms of time-to-recurrence (TTR), overexpression of CASP3, TRAIL-R1, and BAX had a longer TTR than low expression, and overexpression of survivin, MDM2, and BCL2 had a shorter TTR than low expression (P<0.05). Additionally, overexpression of MLL2, UTX, and JMJ5 had shorter TTRs than low expression, and overexpression of KDM5c had a longer TTR than low expression. However, in the multi-variate analysis of predicting factors for recurrence, low expression of CASP3 (P<0.001), and BAX (P<0.001), and overexpression of survivin (P=0.007), and MDM2 (P=0.037) were associated with recurrence independently, but any enzymes modifying histone were not associated with recurrence. Conclusively, this study suggests certain apoptosis-associated factors should be associated with recurrence of AMs, which may be regulated epigenetically by histone modifying enzymes.
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Affiliation(s)
- Sang Hyuk Lee
- Department of Neurosurgery and Division of Neurooncology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Eun Hee Lee
- Department of Pathology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Sung-Hun Lee
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Young Min Lee
- Department of Neurosurgery and Division of Neurooncology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
| | - Hyung Dong Kim
- Department of Neurosurgery, Dong-A University Medical Center, Dong-A University College of Medicine, Busan, Korea
| | - Young Zoon Kim
- Department of Neurosurgery and Division of Neurooncology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea
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Epigallocatechin-3-gallate enhances the therapeutic effects of leptomycin B on human lung cancer a549 cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2015; 2015:217304. [PMID: 25922640 PMCID: PMC4397486 DOI: 10.1155/2015/217304] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2014] [Revised: 03/16/2015] [Accepted: 03/17/2015] [Indexed: 12/20/2022]
Abstract
Our previous studies have shown Leptomycin B (LMB) is a promising antilung cancer drug. Epigallocatechin-3-gallate (EGCG) has antitumor properties but a debatable clinical application. The objective of this study is to evaluate the combination therapeutic effect of LMB and EGCG and its molecular mechanisms in human lung cancer A549 cells. Increased cytotoxicity was observed in LMB+EGCG-treated cells compared to LMB-treated cells. Elevated ROS was maximized 2 h after treatment, and LMB+EGCG-treated cells had higher ROS levels compared to LMB. N-Acetyl-L-cysteine (NAC) studies confirmed the oxidative role of LMB and/or EGCG treatment. In comparison to the control, CYP3A4, SOD, GPX1, and p21 mRNA expression levels were increased 7.1-, 2.0-, 4.6-, and 13.1-fold in LMB-treated cells, respectively, while survivin was decreased 42.6-fold. Additionally, these increases of CYP3A4, SOD, and GPX1 were significantly reduced, while p21 was significantly increased in LMB+EGCG-treated cells compared to LMB-treated cells. The qRT-PCR results for p21 and survivin were further confirmed by Western blot. Our study first shows that LMB produces ROS and is possibly metabolized by CYP3A4, GPX1, and SOD in A549 cells, and combination treatment of LMB and EGCG augments LMB-induced cytotoxicity through enhanced ROS production and the modulation of drug metabolism and p21/survivin pathways.
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12
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Liu Y, Miao C, Wang Z, He X, Shen W. Survivin small interfering RNA suppresses glioblastoma growth by inducing cellular apoptosis. Neural Regen Res 2015; 7:924-31. [PMID: 25722677 PMCID: PMC4341288 DOI: 10.3969/j.issn.1673-5374.2012.12.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2011] [Accepted: 03/20/2012] [Indexed: 01/14/2023] Open
Abstract
A survivin small interfering RNA sequence specific for a human and mouse homogenous sequence was constructed. Survivin small interfering RNA could significantly inhibit glioma cell proliferation and induce apoptosis when it was transfected into either a human glioma cell line U251 or rat glioma C6 cells in vitro. In addition, treatment of rat orthotopic glioma models with survivin small interfering demonstrated the inhibition of glioma growth in vivo. Our experimental findings suggest that the use of RNA interference techniques to target the survivin sequence may be useful in the treatment of glioma.
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Affiliation(s)
- Yanbo Liu
- Beihua University Faculty of Medicine, Jilin 132013, Jilin Province, China
| | - Chunming Miao
- Beihua University Faculty of Medicine, Jilin 132013, Jilin Province, China
| | - Zhenjiang Wang
- Beihua University Faculty of Medicine, Jilin 132013, Jilin Province, China
| | - Xin He
- Beihua University Faculty of Medicine, Jilin 132013, Jilin Province, China
| | - Weigao Shen
- Beihua University Faculty of Medicine, Jilin 132013, Jilin Province, China
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Kolberg M, Høland M, Lind GE, Ågesen TH, Skotheim RI, Hall KS, Mandahl N, Smeland S, Mertens F, Davidson B, Lothe RA. Protein expression of BIRC5, TK1, and TOP2A in malignant peripheral nerve sheath tumours--A prognostic test after surgical resection. Mol Oncol 2015; 9:1129-39. [PMID: 25769404 PMCID: PMC5528761 DOI: 10.1016/j.molonc.2015.02.005] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Revised: 01/22/2015] [Accepted: 02/10/2015] [Indexed: 11/26/2022] Open
Abstract
No consensus treatment regime exists beyond surgery for malignant peripheral nerve sheath tumours (MPNST), and the purpose of the present study was to find new approaches to stratify patients with good and poor prognosis and to better guide therapeutic intervention for this aggressive soft tissue cancer. From a total of 67 MPNSTs from Scandinavian patients with and without neurofibromatosis type 1, 30 MPNSTs were investigated by genome‐wide RNA expression profiling and 63 MPNSTs by immunohistochemical (IHC) analysis, and selected genes were submitted to analyses of disease‐specific survival. The potential drug target genes survivin (BIRC5), thymidine kinase 1 (TK1), and topoisomerase 2‐alpha (TOP2A), all encoded on chromosome arm 17q, were up‐regulated in MPNST as compared to benign neurofibromas. Each of them was found to be independent prognostic markers on the gene expression level, as well as on the protein level. A prognostic profile was identified by combining the nuclear expression scores of the three proteins. For patients with completely resected tumours only 15% in the high risk group were alive after two years, as compared to 78% in the low risk group. In conclusion, we found a novel protein expression profile which identifies MPNST patients with inferior prognosis even after assumed curative surgery. The tested proteins are drug targets; therefore the expression profile may provide predictive information guiding the design of future clinical trials. Importantly, as the effect is seen on the protein level using IHC, the biomarker panel can be readily implemented in routine clinical testing.
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Affiliation(s)
- Matthias Kolberg
- Department of Molecular Oncology, Institute for Cancer Research, Division of Cancer Medicine Surgery and Transplantation, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Maren Høland
- Department of Molecular Oncology, Institute for Cancer Research, Division of Cancer Medicine Surgery and Transplantation, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway
| | - Guro E Lind
- Department of Molecular Oncology, Institute for Cancer Research, Division of Cancer Medicine Surgery and Transplantation, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway
| | - Trude H Ågesen
- Department of Molecular Oncology, Institute for Cancer Research, Division of Cancer Medicine Surgery and Transplantation, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Rolf I Skotheim
- Department of Molecular Oncology, Institute for Cancer Research, Division of Cancer Medicine Surgery and Transplantation, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Kirsten Sundby Hall
- Department of Oncology, Division of Cancer Medicine Surgery and Transplantation, Oslo University Hospital, Oslo, Norway
| | - Nils Mandahl
- Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden
| | - Sigbjørn Smeland
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Oncology, Division of Cancer Medicine Surgery and Transplantation, Oslo University Hospital, Oslo, Norway
| | - Fredrik Mertens
- Department of Clinical Genetics, Skåne University Hospital, Lund, Sweden
| | - Ben Davidson
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Pathology, Division of Diagnostics and Intervention, Oslo University Hospital, Oslo, Norway
| | - Ragnhild A Lothe
- Department of Molecular Oncology, Institute for Cancer Research, Division of Cancer Medicine Surgery and Transplantation, Oslo University Hospital, Oslo, Norway; Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
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14
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Huang L, Liu X, Cheng B, Huang K. How our bodies fight amyloidosis: effects of physiological factors on pathogenic aggregation of amyloidogenic proteins. Arch Biochem Biophys 2015; 568:46-55. [PMID: 25615529 DOI: 10.1016/j.abb.2015.01.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Revised: 01/08/2015] [Accepted: 01/11/2015] [Indexed: 12/15/2022]
Abstract
The process of protein aggregation from soluble amyloidogenic proteins to insoluble amyloid fibrils plays significant roles in the onset of over 30 human amyloidogenic diseases, such as Prion disease, Alzheimer's disease and type 2 diabetes mellitus. Amyloid deposits are commonly found in patients suffered from amyloidosis; however, such deposits are rarely seen in healthy individuals, which may be largely attributed to the self-regulation in vivo. A vast number of physiological factors have been demonstrated to directly affect the process of amyloid formation in vivo. In this review, physiological factors that influence amyloidosis, including biological factors (chaperones, natural antibodies, enzymes, lipids and saccharides) and physicochemical factors (metal ions, pH environment, crowding and pressure, etc.), together with the mechanisms underlying these proteostasis effects, are summarized.
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Affiliation(s)
- Lianqi Huang
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China
| | - Xinran Liu
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China
| | - Biao Cheng
- Department of Pharmacy, Central Hospital of Wuhan, Wuhan, Hubei 430014, PR China
| | - Kun Huang
- Tongji School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China; Centre for Biomedicine Research, Wuhan Institute of Biotechnology, Wuhan, Hubei 430075, PR China.
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15
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Fenstermaker RA, Ciesielski MJ. Challenges in the development of a survivin vaccine (SurVaxM) for malignant glioma. Expert Rev Vaccines 2014; 13:377-85. [PMID: 24521310 DOI: 10.1586/14760584.2014.881255] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
There is growing interest in immunotherapy for malignant gliomas. This interest stems from a number of immunological observations, together with the failure of conventional therapeutic agents to produce broad and clinically meaningful improvements in survival and quality of life. The challenges faced in translating laboratory-based immunological observations to Phase I and II clinical trials for immunotherapy of gliomas are substantial. Nevertheless, as our understanding of the effects of active specific vaccination in glioma patients grows, results support optimism that such methods may eventually prove useful as an adjunctive treatment for these cancers. This paper highlights a number of barriers encountered in the translational development of a survivin-targeted peptide vaccine (SurVaxM) for patients with malignant gliomas.
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Affiliation(s)
- Robert A Fenstermaker
- Department of Neurosurgery, Roswell Park Cancer Institute and State University of New York School of Medicine and Biomedical Sciences, Elm and Carlton Streets, Buffalo, NY 14263, USA
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16
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Mallolas J, Rodríguez R, Gubern C, Camós S, Serena J, Castellanos M. A Polymorphism in the Promoter Region of the Survivin Gene is Related to Hemorrhagic Transformation in Patients with Acute Ischemic Stroke. Neuromolecular Med 2014; 16:856-61. [DOI: 10.1007/s12017-014-8333-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2014] [Accepted: 10/16/2014] [Indexed: 10/24/2022]
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17
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Wang W, Li Z, Duan J, Wang C, Fang Y, Yang XD. In vitro enhancement of dendritic cell-mediated anti-glioma immune response by graphene oxide. NANOSCALE RESEARCH LETTERS 2014; 9:311. [PMID: 25024678 PMCID: PMC4082417 DOI: 10.1186/1556-276x-9-311] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Accepted: 06/11/2014] [Indexed: 06/03/2023]
Abstract
Malignant glioma has extremely poor prognosis despite combination treatments with surgery, radiation, and chemotherapy. Dendritic cell (DC)-based immunotherapy may potentially serve as an adjuvant treatment of glioma, but its efficacy generally needs further improvement. Here we explored whether graphene oxide (GO) nanosheets could modulate the DC-mediated anti-glioma immune response in vitro, using the T98G human glioma cell line as the study model. Pulsing DCs with a glioma peptide antigen (Ag) generated a limited anti-glioma response compared to un-pulsed DCs. Pulsing DCs with GO alone failed to produce obvious immune modulation effects. However, stimulating DCs with a mixture of GO and Ag (GO-Ag) significantly enhanced the anti-glioma immune reaction (p < 0.05). The secretion of interferon gamma (IFN-γ) by the lymphocytes was also markedly boosted by GO-Ag. Additionally, the anti-glioma immune response induced by GO-Ag appeared to be target-specific. Furthermore, at the concentration used in this study, GO exhibited a negligible effect on the viability of the DCs. These results suggested that GO might have potential utility for boosting a DC-mediated anti-glioma immune response.
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Affiliation(s)
- Wei Wang
- Peking University People’s Hospital, Peking University Hepatology Institute, Beijing 100044, China
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Zhongjun Li
- National Center for Nanoscience and Technology, Beijing 100190, China
| | - Jinhong Duan
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
| | - Chen Wang
- National Center for Nanoscience and Technology, Beijing 100190, China
| | - Ying Fang
- National Center for Nanoscience and Technology, Beijing 100190, China
| | - Xian-Da Yang
- Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100005, China
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18
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Shafie INF, McLaughlin M, Burchmore R, Lim MAA, Montague P, Johnston PEJ, Penderis J, Anderson TJ. The chaperone protein clusterin may serve as a cerebrospinal fluid biomarker for chronic spinal cord disorders in the dog. Cell Stress Chaperones 2014; 19:311-20. [PMID: 23990410 PMCID: PMC3982024 DOI: 10.1007/s12192-013-0457-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Revised: 08/14/2013] [Accepted: 08/15/2013] [Indexed: 12/13/2022] Open
Abstract
Chronic spinal cord dysfunction occurs in dogs as a consequence of diverse aetiologies, including long-standing spinal cord compression and insidious neurodegenerative conditions. One such neurodegenerative condition is canine degenerative myelopathy (DM), which clinically is a challenge to differentiate from other chronic spinal cord conditions. Although the clinical diagnosis of DM can be strengthened by the identification of the Sod1 mutations that are observed in affected dogs, genetic analysis alone is insufficient to provide a definitive diagnosis. There is a requirement to identify biomarkers that can differentiate conditions with a similar clinical presentation, thus facilitating patient diagnostic and management strategies. A comparison of the cerebrospinal fluid (CSF) protein gel electrophoresis profile between idiopathic epilepsy (IE) and DM identified a protein band that was more prominent in DM. This band was subsequently found to contain a multifunctional protein clusterin (apolipoprotein J) that is protective against endoplasmic reticulum (ER) stress-mediated apoptosis, oxidative stress, and also serves as an extracellular chaperone influencing protein aggregation. Western blot analysis of CSF clusterin confirmed elevated levels in DM compared to IE (p < 0.05). Analysis of spinal cord tissue from DM and control material found that clusterin expression was evident in neurons and that the clusterin mRNA levels from tissue extracts were elevated in DM compared to the control. The plasma clusterin levels was comparable between these groups. However, a comparison of clusterin CSF levels in a number of neurological conditions found that clusterin was elevated in both DM and chronic intervertebral disc disease (cIVDD) but not in meningoencephalitis and IE. These findings indicate that clusterin may potentially serve as a marker for chronic spinal cord disease in the dog; however, additional markers are required to differentiate DM from a concurrent condition such as cIVDD.
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Affiliation(s)
- Intan N. F. Shafie
- />School of Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden Road, Glasgow, G61 1QH UK
- />Faculty of Veterinary Medicine, University Putra Malaysia, 43400 Serdang, Selangor Malaysia
| | - Mark McLaughlin
- />School of Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden Road, Glasgow, G61 1QH UK
| | - Richard Burchmore
- />Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G12 8TA Scotland UK
- />Glasgow Polyomics, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, Scotland UK
| | - Mary Ann A. Lim
- />School of Life Sciences and Chemical Technology, Ngee Ann Polytechnic, 599489 Singapore, Singapore
| | - Paul Montague
- />Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, G12 8TA Scotland UK
| | - Pamela E. J. Johnston
- />School of Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden Road, Glasgow, G61 1QH UK
| | - Jacques Penderis
- />School of Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden Road, Glasgow, G61 1QH UK
| | - Thomas J. Anderson
- />School of Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden Road, Glasgow, G61 1QH UK
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Caspase-3 and survivin expression in primary atypical and malignant meningiomas. ISRN NEUROSCIENCE 2013; 2013:626290. [PMID: 25006573 PMCID: PMC4061719 DOI: 10.1155/2013/626290] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/14/2012] [Accepted: 12/04/2012] [Indexed: 11/17/2022]
Abstract
Objective. Information about possible prognostic factors of the survival of patients with atypical and malignant meningiomas (AMM) is sparse. The aim of our study was to evaluate prognostic significance of apoptotic marker caspase-3 and apoptotic inhibitor survivin in a series of primary AMM. Methods. 86 AMM (76 atypical and 10 malignant) were analyzed. Caspase-3 and survivin expression was evaluated immunohistochemically. The correlation between caspase-3, survivin, and other possible factors of meningioma recurrence was evaluated. Uni- and multivariate recurrence-free survival (RFS) and overall survival (OS) analyses were performed. Results. The intensity of caspase-3 expression correlated with the tumor grade (P = 0.004), the proliferation index (P = 0.019), and the mitotic count (P = 0.013). Survivin tended to be more expressed in female patients (P = 0.072). Survivin expression was stronger in malignant compared to atypical meningiomas, however, the difference was not statistically important (P = 0.491). Neither survivin nor caspase-3 expression significantly predicted OS or RFS in patients with AMM. Conclusions. Strong caspase-3 expression on AMM cells could reflect a cellular attempt at the homeostatic autoregulation of the tumor size. Survivin expression on AMM cells is similar to the survivin expression reported on benign meningiomas. Caspase-3 and survivin expression has no prognostic significance on the survival of patients with AMM.
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20
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Maarouf CL, Beach TG, Adler CH, Shill HA, Sabbagh MN, Wu T, Walker DG, Kokjohn TA, Roher AE. Cerebrospinal fluid biomarkers of neuropathologically diagnosed Parkinson's disease subjects. Neurol Res 2013; 34:669-76. [PMID: 22889670 DOI: 10.1179/1743132812y.0000000063] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
OBJECTIVES Parkinson's disease (PD) afflicts approximately 1-2% of the population over 50 years of age. No cures or effective modifying treatments exist and clinical diagnosis is currently confounded by a lack of definitive biomarkers. We sought to discover potential biomarkers in the cerebrospinal fluid (CSF) of neuropathologically confirmed PD cases. METHODS We compared postmortem ventricular CSF (V-CSF) from PD and normal control (NC) subjects using two-dimensional difference gel electrophoresis (2D-DIGE). Spots exhibiting a 1·5-fold or greater difference in volume between PD patients and controls were excised from the two-dimensional gels, subjected to tryptic digestion and identification of peptides assigned using mass spectrometric/data bank correlation methods. RESULTS Employing this strategy six molecules: fibrinogen, transthyretin, apolipoprotein E, clusterin, apolipoprotein A-1, and glutathione-S-transferase-Pi, were found to be different between PD and NC populations. DISCUSSION These molecules have been implicated in PD pathogenesis. Combining biomarker data from multiple laboratories may create a consensus panel of proteins that may serve as a diagnostic tool for this neurodegenerative disorder.
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Affiliation(s)
- Chera L Maarouf
- The Longtine Center for Neurodegenerative Biochemistry, Banner Sun Health Research Institute, Sun City, AZ, USA
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21
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Resnier P, Montier T, Mathieu V, Benoit JP, Passirani C. A review of the current status of siRNA nanomedicines in the treatment of cancer. Biomaterials 2013; 34:6429-43. [PMID: 23727262 DOI: 10.1016/j.biomaterials.2013.04.060] [Citation(s) in RCA: 162] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2013] [Accepted: 04/27/2013] [Indexed: 12/11/2022]
Abstract
RNA interference currently offers new opportunities for gene therapy by the specific extinction of targeted gene(s) in cancer diseases. However, the main challenge for nucleic acid delivery still remains its efficacy through intravenous administration. Over the last decade, many delivery systems have been developed and optimized to encapsulate siRNA and to specifically promote their delivery into tumor cells and improve their pharmacokinetics for anti-cancer purposes. This review aims to sum up the potential targets in numerous pathways and the properties of recently optimized siRNA synthetic nanomedicines with their preclinical applications and efficacy. Future perspectives in cancer treatment are discussed including promising concomitant treatment with chemotherapies or other siRNA. The outcomes in human clinical trials are also presented.
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22
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Abdel-Aziz A, Mohamed MAA, Akl FMF, Taha ANM. Survivin expression in medulloblastoma: a possible marker for survival. Pathol Oncol Res 2012; 19:413-9. [PMID: 23242569 DOI: 10.1007/s12253-012-9594-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2012] [Accepted: 11/19/2012] [Indexed: 01/23/2023]
Abstract
UNLABELLED Medulloblastomas are highly invasive tumors which are generally disseminated at the time of diagnosis. High and continued morbidity and mortality have prompted the search for new biologic markers that might be used for targeted therapy to minimise treatment related side effects. In this work, we studied the positive expression of survivin in medulloblastoma and investigated its relation to clinical, pathologic data and survival. Tumor tissue specimens from 47 patients with medulloblastoma who underwent primary surgical treatment from June 2002 to June 2006 at the Mansoura university hospital, Egypt were collected. Paraffin sections of all samples were submitted for immunohistochemistry using anti-survivin antibody. The relation between the percentage of positive survivin cells with clinical, pathological and survival data was evaluated. RESULTS In 47 cancer tissue specimens, one case large-cell-anaplastic (1.12 %), tweleve cases desmoplastic (25.53 %) and 34 cases classic medulloblastomas (72.34 %). The immunohistochemical expression of survivin was nulear with moderate intensity. It does not correlate with either age or sex. There was a significant negative correlation of survivin expression with survival (p < 0.001), where negative survivin immunostaining was associated with prolonged overall and disease free survival, while survivin expression was associated with shortened survival. CONCLUSION Survivin expression correlate with the clinical outcome with poor prognosis and could be a potential predictive factor for recurrence or metastasis.
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Affiliation(s)
- Azza Abdel-Aziz
- Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
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23
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Fermented mistletoe extract as a multimodal antitumoral agent in gliomas. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2012; 2012:501796. [PMID: 23133496 PMCID: PMC3485514 DOI: 10.1155/2012/501796] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2012] [Accepted: 09/05/2012] [Indexed: 01/03/2023]
Abstract
In Europe, commercially available extracts from the white-berry mistletoe (Viscum album L.) are widely used as a complementary cancer therapy. Mistletoe lectins have been identified as main active components and exhibit cytotoxic effects as well as immunomodulatory activity. Since it is still not elucidated in detail how mistle toe extracts such as ISCADOR communicate their effects, we analyzed the mechanisms that might be responsible for their antitumoral function on a molecular and functional level. ISCADOR-treated glioblastoma (GBM) cells down-regulate central genes involved in glioblastoma progression and malignancy such as the cytokine TGF-β and matrix-metalloproteinases. Using in vitro glioblastoma/immune cell co-cultivation assays as well as measurement of cell migration and invasion, we could demonstrate that in glioblastoma cells, lectin-rich ISCADOR M and ISCADOR Q significantly enforce NK-cell-mediated GBM cell lysis. Beside its immune stimulatory effect, ISCADOR reduces the migratory and invasive potential of glioblastoma cells. In a syngeneic as well as in a xenograft glioblastoma mouse model, both pretreatment of tumor cells and intratumoral therapy of subcutaneously growing glioblastoma cells with ISCADOR Q showed delayed tumor growth. In conclusion, ISCADOR Q, showing multiple positive effects in the treatment of glioblastoma, may be a candidate for concomitant treatment of this cancer.
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Charnay Y, Imhof A, Vallet PG, Kovari E, Bouras C, Giannakopoulos P. Clusterin in neurological disorders: Molecular perspectives and clinical relevance. Brain Res Bull 2012; 88:434-43. [DOI: 10.1016/j.brainresbull.2012.05.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2012] [Accepted: 05/07/2012] [Indexed: 10/28/2022]
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25
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Wakabayashi K, Tanji K, Odagiri S, Miki Y, Mori F, Takahashi H. The Lewy body in Parkinson's disease and related neurodegenerative disorders. Mol Neurobiol 2012; 47:495-508. [PMID: 22622968 DOI: 10.1007/s12035-012-8280-y] [Citation(s) in RCA: 297] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2012] [Accepted: 05/10/2012] [Indexed: 12/20/2022]
Abstract
The histopathological hallmark of Parkinson's disease (PD) is the presence of fibrillar aggregates referred to as Lewy bodies (LBs), in which α-synuclein is a major constituent. Pale bodies, the precursors of LBs, may serve the material for that LBs continue to expand. LBs consist of a heterogeneous mixture of more than 90 molecules, including PD-linked gene products (α-synuclein, DJ-1, LRRK2, parkin, and PINK-1), mitochondria-related proteins, and molecules implicated in the ubiquitin-proteasome system, autophagy, and aggresome formation. LB formation has been considered to be a marker for neuronal degeneration because neuronal loss is found in the predilection sites for LBs. However, recent studies have indicated that nonfibrillar α-synuclein is cytotoxic and that fibrillar aggregates of α-synuclein (LBs and pale bodies) may represent a cytoprotective mechanism in PD.
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Affiliation(s)
- Koichi Wakabayashi
- Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan.
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Faccion RS, Ferreira RM, Grabois MF, Fonseca TC, de Oliveira JA, Maia RC. Lack of Prognostic Significance of Survivin in Pediatric Medulloblastoma. Pathol Oncol Res 2011; 17:899-908. [DOI: 10.1007/s12253-011-9401-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2011] [Accepted: 04/06/2011] [Indexed: 11/29/2022]
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Anandharaj A, Cinghu S, Park WY. Rapamycin-mediated mTOR inhibition attenuates survivin and sensitizes glioblastoma cells to radiation therapy. Acta Biochim Biophys Sin (Shanghai) 2011; 43:292-300. [PMID: 21367753 DOI: 10.1093/abbs/gmr012] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Survivin, an antiapoptotic protein, is elevated in most malignancies and attributes to radiation resistance in tumors including glioblastoma multiforme. The downregulation of survivin could sensitize glioblastoma cells to radiation therapy. In this study, we investigated the effect of rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), in attenuating survivin and enhancing the therapeutic efficacy for glioblastoma cells, and elucidated the underlying mechanisms. Here we tested various concentrations of rapamycin (1-8 nM) in combination with radiation dose 4 Gy. Rapamycin effectively modulated the protein kinase B (Akt)/mTOR pathway by inhibiting the phosphorylation of Akt and mTOR proteins, and this inhibition was further enhanced by radiation. The expression level of survivin was decreased in rapamycin pre-treatment glioblastoma cells followed by radiation; meanwhile, the phosphorylation of H2A histone family member X (H2AX) at serine-139 (γ-H2AX) was increased. p21 protein was also induced on radiation with rapamycin pre-treatment, which enhanced G1 arrest and the accumulation of cells at G0/subG1 phase. Furthermore, the clonogenic cell survival assay revealed a significant dose-dependent decrease in the surviving fraction for all three cell lines pre-treated with rapamycin. Our studies demonstrated that targeting survivin may be an effective approach for radiosensitization of malignant glioblastoma.
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Affiliation(s)
- Arunkumar Anandharaj
- Department of Radiation Oncology, Chungbuk National University College of Medicine, Cheongju, Korea
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Identification of gene markers associated with aggressive meningioma by filtering across multiple sets of gene expression arrays. J Neuropathol Exp Neurol 2011; 70:1-12. [PMID: 21157382 DOI: 10.1097/nen.0b013e3182018f1c] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Meningiomas are common intracranial tumors, but relatively little is known about the genetic events responsible for their clinical diversity. Although recent genomic studies have provided clues, the genes identified often differ among publications. We used microarray expression profiling to identify genes that are differentially expressed, with at least a 4-fold change, between grade I and grade III meningiomas. We filtered this initial set of potential biomarkers through a second cohort of meningiomas and then verified the remaining genes by quantitative polymerase chain reaction followed by examination using a third microarray expression cohort. Using this approach, we identified 9 overexpressed (TPX2, RRM2, TOP2A, PI3, BIRC5, CDC2, NUSAP1, DLG7, SOX11) and 2 underexpressed (TIMP3, KCNMA1) genes in grade III versus grade I meningiomas. As a further validation step, we analyzed these genes in a fourth cohort and found that patients with grade II meningiomas with high topoisomerase 2-α protein expressions (>5% labeling index) had shorter times to death than patients with low expressions. We believe that this multistep multi-cohort approach provides a robust method for reducing false-positives while generating a list of reproducible candidate genes that are associated with clinically aggressive meningiomas and are suitable for analysis for their potential prognostic value.
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29
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Eisele G, Weller M. Targeting apoptosis pathways in glioblastoma. Cancer Lett 2011; 332:335-45. [PMID: 21269762 DOI: 10.1016/j.canlet.2010.12.012] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2010] [Revised: 12/12/2010] [Accepted: 12/14/2010] [Indexed: 01/14/2023]
Abstract
The treatment of glioblastoma remains a major challenge for clinicians since these highly aggressive brain tumors are relatively resistant towards radio- and chemotherapy. The pathways that control apoptosis are altered in glioblastoma cells leading to resistance towards apoptotic stimuli in general. In this review we describe the alterations affecting the p53 pathway, the BCL-2 protein family, the inhibitor of apoptosis proteins and several growth factor pathways involved in the regulation of programmed cell death and define possible targets for new therapies within these apoptotic pathways in glioblastomas. Moreover, we review strategies to target death receptor pathways, most notably to render the glioblastoma cells more susceptible towards this approach without enhancing toxicity in general. Most of the strategies targeting apoptosis in glioblastomas presented here are in a pre-clinical stage of development, however, they all share the ultimative goal to improve the outcome for glioblastoma patients.
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Affiliation(s)
- Günter Eisele
- Department of Neurology, University Hospital Zurich, Frauenklinikstrasse 26, CH-8091 Zurich, Switzerland.
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Abstract
The maintenance of the levels and correct folding state of proteins (proteostasis) is a fundamental prerequisite for life. Life has evolved complex mechanisms to maintain proteostasis and many of these that operate inside cells are now well understood. The same cannot yet be said of corresponding processes in extracellular fluids of the human body, where inappropriate protein aggregation is known to underpin many serious diseases such as Alzheimer's disease, type II diabetes and prion diseases. Recent research has uncovered a growing family of abundant extracellular chaperones in body fluids which appear to selectively bind to exposed regions of hydrophobicity on misfolded proteins to inhibit their toxicity and prevent them from aggregating to form insoluble deposits. These extracellular chaperones are also implicated in clearing the soluble, stabilized misfolded proteins from body fluids via receptor-mediated endocytosis for subsequent lysosomal degradation. Recent work also raises the possibility that extracellular chaperones may play roles in modulating the immune response. Future work will better define the in vivo functions of extracellular chaperones in proteostasis and immunology and pave the way for the development of new treatments for serious diseases.
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31
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Dabbs RA, Wyatt AR, Yerbury JJ, Ecroyd H, Wilson MR. Extracellular Chaperones. Top Curr Chem (Cham) 2010. [PMID: 21516385 DOI: 10.1007/128_2010_85] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The maintenance of the levels and correct folding state of proteins (proteostasis) is a fundamental prerequisite for life. Life has evolved complex mechanisms to maintain proteostasis and many of these that operate inside cells are now well understood. The same cannot yet be said of corresponding processes in extracellular fluids of the human body, where inappropriate protein aggregation is known to underpin many serious diseases such as Alzheimer's disease, type II diabetes and prion diseases. Recent research has uncovered a growing family of abundant extracellular chaperones in body fluids which appear to selectively bind to exposed regions of hydrophobicity on misfolded proteins to inhibit their toxicity and prevent them from aggregating to form insoluble deposits. These extracellular chaperones are also implicated in clearing the soluble, stabilized misfolded proteins from body fluids via receptor-mediated endocytosis for subsequent lysosomal degradation. Recent work also raises the possibility that extracellular chaperones may play roles in modulating the immune response. Future work will better define the in vivo functions of extracellular chaperones in proteostasis and immunology and pave the way for the development of new treatments for serious diseases.
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Kernt M, Neubauer AS, Eibl KH, Wolf A, Ulbig MW, Kampik A, Hirneiss C. Minocycline is cytoprotective in human trabecular meshwork cells and optic nerve head astrocytes by increasing expression of XIAP, survivin, and Bcl-2. Clin Ophthalmol 2010; 4:591-604. [PMID: 20668721 PMCID: PMC2909888 DOI: 10.2147/opth.s11216] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2010] [Indexed: 01/17/2023] Open
Abstract
INTRODUCTION Primary open-angle glaucoma (POAG) is one of the leading causes of blindness. Activation of optic nerve head astrocytes (ONHA) and loss of trabecular meshwork cells (TMC) are pathognomonic for this neurodegenerative disease. Oxidative stress and elevated levels of transforming growth factor beta (TGFbeta) play an important role in the pathogenesis of POAG. This study investigates the possible antiapoptotic and cytoprotective effects of minocycline on TMC and ONHA under oxidative stress and increased TGFbeta levels. METHODS TMC and ONHA were treated with minocycline 1-150 muM. Possible toxic effects and IC(50) were evaluated after 48 hours. Cell proliferation and viability were examined in order to assess the protective effects of minocycline on TMC and ONHA. Expression of Bcl-2, XIAP, and survivin, as well as their mRNA expression, were assessed by real time polymerase chain reaction (RT-PCR) and Western Blot analysis 48 hours after treatment with minocycline alone and additional incubation with TGFbeta-2 or oxidative stress. RESULTS Minocycline 1-75 muM showed no toxic effects on TMC and ONHA. Under conditions of oxidative stress, both TMC and ONHA showed an increase in viability and an ability to proliferate when treated with minocycline 20-40 muM. RT-PCR and Western blotting yielded an overexpression of Bcl-2, XIAP, and survivin when TMC or ONHA were treated with minocycline 20-40 muM under conditions of oxidative stress and when additionally incubated with TGFbeta-2. CONCLUSION Minocycline up to 75 muM does not have toxic effects on TMC and ONHA. Treatment with minocycline 20-40 muM led to increased viability and proliferation under oxidative stress and TGFbeta-2, as well as overexpression of Bcl-2, XIAP, and survivin. This protective pathway may help to prevent apoptotic cell death of TMC and ONHA and therefore be a promising approach to avoidance of progression of glaucomatous degeneration.
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Affiliation(s)
- Marcus Kernt
- Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany
| | | | - Kirsten H Eibl
- Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany
| | - Armin Wolf
- Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany
| | - Michael W Ulbig
- Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany
| | - Anselm Kampik
- Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany
| | - Cristoph Hirneiss
- Department of Ophthalmology, Ludwig-Maximilians-University, Munich, Germany
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Signals of apoptotic pathways in several types of meningioma. Pathol Oncol Res 2010; 17:51-9. [PMID: 20524098 DOI: 10.1007/s12253-010-9279-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2009] [Accepted: 05/18/2010] [Indexed: 10/19/2022]
Abstract
Meningiomas are intracranial tumour derived from meningothelial cells, which aggressive behaviour has been frequently associated to cell apoptosis. In this paper activation of several factors involved in apoptosis has been investigated on biopsies of primary, non recurrent meningiomas. Benign (meningotheliomatous, transitional, fibrous, angiomatous), atypical and anaplastic meningiomas were analysed by immunohistochemistry and western blot, to visualize the occurring of different apoptotic pathways and their association with clinical grading. Apoptotic cell have been detected by a double colorimetric staining for TUNEL and caspase-3 active form. Apoptotic signal positive cells have been detected in all type of meningiomas analysed, with exception of meningotheliomatous meningiomas. Differences have been found in the activation of apoptotic pathways between several types of grade I meningiomas and among benign, anaplastic and atypical meningiomas. An intense expression of several apoptotic inhibitor occurred in grade I meningiomas. The correlation among expression of apoptotic and inhibitory factors and cell proliferation index may suggest that in grade I meningiomas apoptosis may be related to mechanisms involved into tumor cells surviving. Instead in grade II and III meningiomas the same correlation seems indicate an high turnover of tumor cells that might be useful as index of cell proliferation and tumor mass growth.
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Liu R, Mitchell DA. Survivin as an immunotherapeutic target for adult and pediatric malignant brain tumors. Cancer Immunol Immunother 2010; 59:183-93. [PMID: 19756596 PMCID: PMC11030045 DOI: 10.1007/s00262-009-0757-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2009] [Accepted: 08/18/2009] [Indexed: 12/22/2022]
Affiliation(s)
- Rebecca Liu
- The Preston Robert Tisch Brain Tumor Center at Duke, Durham, NC, USA.
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Polyploidy: Mechanisms and Cancer Promotion in Hematopoietic and Other Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2010; 676:105-22. [DOI: 10.1007/978-1-4419-6199-0_7] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Shehata HH, Abou Ghalia AH, Elsayed EK, Ziko OO, Mohamed SS. Detection of survivin protein in aqueous humor and serum of retinoblastoma patients and its clinical significance. Clin Biochem 2009; 43:362-6. [PMID: 19913527 DOI: 10.1016/j.clinbiochem.2009.10.056] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2009] [Revised: 10/26/2009] [Accepted: 10/27/2009] [Indexed: 12/21/2022]
Abstract
OBJECTIVES There is growing biomedical interest in survivin as a diagnostic and prognostic factor in human neoplasms. The present work assessed survivin expression in retinoblastoma. DESIGN AND METHODS Survivin was quantitatively measured in 82 aqueous humor and serum samples from 41 children with retinoblastoma and nonmalignant ophthalmic diseases. After treatment, 12 serum samples from retinoblastoma patients were included. RESULTS Survivin levels were higher in aqueous humor and serum of retinoblastoma patients than the controls (P<0.05). In aqueous, it was significantly correlated with the tumor stage and optic nerve affection. The best cutoff values for survivin in aqueous and serum that differentiate between retinoblastoma and nonmalignant ophthalmic diseases were 25.2 pg/mg protein and 12.9 pg/mL, respectively. The sensitivity and specificity were 100% and 90% in serum and 94% and 48% in aqueous, respectively. Serum survivin has decreased significantly after treatment. CONCLUSION Measurement of survivin protein might have a great diagnostic and prognostic potential in retinoblastoma.
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Affiliation(s)
- Hanan H Shehata
- Medical Biochemistry Department, Ain Shams Faculty of Medicine, Abbassia, Cairo, Egypt.
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37
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Jacobs JFM, Coulie PG, Figdor CG, Adema GJ, de Vries IJM, Hoogerbrugge PM. Targets for active immunotherapy against pediatric solid tumors. Cancer Immunol Immunother 2009; 58:831-41. [PMID: 19009292 PMCID: PMC11030767 DOI: 10.1007/s00262-008-0619-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2008] [Accepted: 10/22/2008] [Indexed: 02/06/2023]
Abstract
The potential role of antibodies and T lymphocytes in the eradication of cancer has been demonstrated in numerous animal models and clinical trials. In the last decennia new strategies have been developed for the use of tumor-specific T cells and antibodies in cancer therapy. Effective anti-tumor immunotherapy requires the identification of suitable target antigens. The expression of tumor-specific antigens has been extensively studied for most types of adult tumors. Pediatric patients should be excellent candidates for immunotherapy since their immune system is more potent and flexible as compared to that of adults. So far, these patients do not benefit enough from the progresses in cancer immunotherapy, and one of the reasons is the paucity of tumor-specific antigens identified on pediatric tumors. In this review we discuss the current status of cancer immunotherapy in children, focusing on the identification of tumor-specific antigens on pediatric solid tumors.
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Affiliation(s)
- J F M Jacobs
- Department of Pediatric Hemato-oncology, Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands.
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Amiri S, Movahedin M, Mowla SJ, Hajebrahimi Z, Tavallaei M. Differential gene expression and alternative splicing of survivin following mouse sciatic nerve injury. Spinal Cord 2009; 47:739-44. [DOI: 10.1038/sc.2009.26] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
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Novel Genomic Alterations and Mechanisms Associated With Tumor Progression in Oligodendroglioma and Mixed Oligoastrocytoma. J Neuropathol Exp Neurol 2009; 68:274-85. [DOI: 10.1097/nen.0b013e31819a3e8c] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
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40
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Balani P, Boulaire J, Zhao Y, Zeng J, Lin J, Wang S. High mobility group box2 promoter-controlled suicide gene expression enables targeted glioblastoma treatment. Mol Ther 2009; 17:1003-11. [PMID: 19240692 DOI: 10.1038/mt.2009.22] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Achievement of specific tumor cell targeting remains a challenge for glioma gene therapy. We observed that the human high mobility group box2 (HMGB2) gene had a low level of expression in normal human brain tissues, but was significantly upregulated in glioblastoma tissues. With progressive truncation of a 5'-upstream sequence of the HMGB2 gene, we identified a 0.5-kb fragment displaying a high transcriptional activity in glioblastoma cells, but a low activity in normal brain cells. To test the feasibility of using the HMGB2 promoter sequence in targeted cancer therapy, we constructed a baculoviral vector expressing the herpes simplex virus thymidine kinase (HSVtk) gene driven by the HMGB2 promoter. Transduction with the viral vector induced cell death in glioblastoma cell lines in the presence of ganciclovir (GCV), but did not affect the survival of human astrocytes and neurons. In a mouse xenograft model, intratumor injection of the baculoviral vector suppressed the growth of human glioblastoma cells and prolonged the survival of tumor-bearing mice. Our results suggest that the novel 5' sequence of HMGB2 gene has a potential to be used as an efficient, tumor-selective promoter in targeted vectors for glioblastoma gene therapy.
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Affiliation(s)
- Poonam Balani
- Institute of Bioengineering and Nanotechnology, Singapore
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41
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Shirai K, Suzuki Y, Oka K, Noda SE, Katoh H, Suzuki Y, Itoh J, Itoh H, Ishiuchi S, Sakurai H, Hasegawa M, Nakano T. Nuclear survivin expression predicts poorer prognosis in glioblastoma. J Neurooncol 2008; 91:353-8. [DOI: 10.1007/s11060-008-9720-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2008] [Accepted: 10/13/2008] [Indexed: 01/17/2023]
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Ciesielski MJ, Kozbor D, Castanaro CA, Barone TA, Fenstermaker RA. Therapeutic effect of a T helper cell supported CTL response induced by a survivin peptide vaccine against murine cerebral glioma. Cancer Immunol Immunother 2008; 57:1827-35. [PMID: 18438666 DOI: 10.1007/s00262-008-0510-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2008] [Accepted: 03/24/2008] [Indexed: 12/23/2022]
Abstract
Survivin is a tumor-associated antigen (TAA) that has significant potential for use as a cancer vaccine target. To identify survivin epitopes that might serve as targets for CTL-mediated, anti-tumor responses, we evaluated a series of survivin peptides with predicted binding to mouse H2-K(b) and human HLA-A*0201 antigens in peptide-loaded dendritic cell (DC) vaccines. H2-K(b)-positive, C57BL/6 mice were vaccinated using syngeneic, peptide-loaded DC2.4 cells. Splenocytes from vaccinated mice were screened by flow cytometry for binding of dimeric H2-K(b):Ig to peptide-specific CD8+ T cells. Two survivin peptides (SVN(57-64) and SVN(82-89)) generated specific CD8+ T cells. We chose to focus on the SVN(57-64) peptide because that region of the molecule is 100% homologous to human survivin. A larger peptide (SVN(53-67)), containing multiple class I epitopes, and a potential class II ligand, was able to elicit both CD8+ CTL and CD4+ T cell help. We tested the SVN(53-67) 15-mer peptide in a therapeutic model using a peptide-loaded DC vaccine in C57BL/6 mice with survivin-expressing GL261 cerebral gliomas. This vaccine produced significant CTL responses and helper T cell-associated cytokine production, resulting in a significant prolongation of survival. The SVN(53-67) vaccine was significantly more effective than the SVN(57-64) core epitope as a cancer vaccine, emphasizing the potential benefit of incorporating multiple class I epitopes and associated cytokine support within a single peptide.
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Affiliation(s)
- Michael J Ciesielski
- Department of Neurosurgery, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA.
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Valle-Folgueral J, Mascarenhas L, Costa J, Alegria C, Vieira F, Soares-Fernandes J, Beleza P. Giant cell glioblastoma: review of the literature and illustrated case. Neurocirugia (Astur) 2008; 19:343-9. [DOI: 10.1016/s1130-1473(08)70221-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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Piña-Oviedo S, Urbanska K, Radhakrishnan S, Sweet T, Reiss K, Khalili K, Del Valle L. Effects of JC virus infection on anti-apoptotic protein survivin in progressive multifocal leukoencephalopathy. THE AMERICAN JOURNAL OF PATHOLOGY 2007; 170:1291-304. [PMID: 17392168 PMCID: PMC1829462 DOI: 10.2353/ajpath.2007.060689] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Progressive multifocal leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system resulting from the productive infection of oligodendrocytes by the opportunistic polyomavirus JC virus (JCV). Apoptosis is a host defense mechanism to dispose of damaged cells; however, certain viruses have the ability to deregulate apoptotic pathways to complete their life cycles. One such pathway involves survivin, a member of the inhibitor of apoptosis family, which is abundantly expressed during development in proliferating tissues but should be absent in normal, terminally differentiated cells. Immunohistochemistry performed in 20 cases of PML revealed the presence of survivin in JCV-infected oligodendrocytes and bizarre astrocytes within demyelinated plaques. Survivin up-regulation was also found in oligodendroglial and astrocytic cultures infected with JCV. Cell cycle analysis and DNA laddering demonstrated a significantly lower number of cells undergoing apoptosis on JCV infection compared with noninfected cultures; small interfering RNA inhibition of survivin resulted in a dramatic increase in apoptotic cells in JCV-infected cultures. This is the first report describing the activation of survivin by JCV infection in vitro and in PML clinical cases. These observations provide new insights into the anti-apoptotic mechanisms used by JCV to complete its lytic cycle and may suggest new therapeutic targets for PML.
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Affiliation(s)
- Sergio Piña-Oviedo
- Department of Neuroscience, Neuropathology Core, Temple University School of Medicine, 1900 North 12th St., Suite 240, Philadelphia, PA 19122, USA
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Zhadobov M, Sauleau R, Le Coq L, Debure L, Thouroude D, Michel D, Le Dréan Y. Low-power millimeter wave radiations do not alter stress-sensitive gene expression of chaperone proteins. Bioelectromagnetics 2007; 28:188-96. [PMID: 17080454 DOI: 10.1002/bem.20285] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
This article reports experimental results on the influence of low-power millimeter wave (MMW) radiation at 60 GHz on a set of stress-sensitive gene expression of molecular chaperones, namely clusterin (CLU) and HSP70, in a human brain cell line. Selection of the exposure frequency is determined by its near-future applications for the new broadband civil wireless communication systems including wireless local area networks (WLAN) for domestic and professional uses. Frequencies around 60 GHz are strongly attenuated in the earth's atmosphere and such radiations represent a new environmental factor. An exposure system operating in V-band (50-75 GHz) was developed for cell exposure. U-251 MG glial cell line was sham-exposed or exposed to MMW radiation for different durations (1-33 h) and two different power densities (5.4 microW/cm(2) or 0.54 mW/cm(2)). As gene expression is a multiple-step process, we analyzed chaperone proteins induction at different levels. First, using luciferase reporter gene, we investigated potential effect of MMWs on the activation of transcription factors (TFs) and gene promoter activity. Next, using RT-PCR and Western blot assays, we verified whether MMW exposure could alter RNA accumulation, translation, or protein stability. Experimental data demonstrated the absence of significant modifications in gene transcription, mRNA, and protein amount for the considered stress-sensitive genes for the exposure durations and power densities investigated. The main results of this study suggest that low-power 60 GHz radiation does not modify stress-sensitive gene expression of chaperone proteins.
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Affiliation(s)
- M Zhadobov
- Institute of Electronics and Telecommunications of Rennes (IETR), University of Rennes I, Campus de Beaulieu, bâtiment 11D, 263 avenue du Général Leclerc, 35042 Rennes Cedex, France.
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Ciesielski MJ, Apfel L, Barone TA, Castro CA, Weiss TC, Fenstermaker RA. Antitumor effects of a xenogeneic survivin bone marrow derived dendritic cell vaccine against murine GL261 gliomas. Cancer Immunol Immunother 2006; 55:1491-503. [PMID: 16485128 PMCID: PMC11030856 DOI: 10.1007/s00262-006-0138-6] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2005] [Accepted: 12/30/2005] [Indexed: 11/30/2022]
Abstract
Survivin is a member of the inhibitor of apoptosis protein family. Gliomas and many other tumors express survivin at high levels; whereas, normal fully differentiated cells generally do not. Therefore, survivin represents a tumor-specific target for cancer vaccine therapy. It has been shown that it is possible to produce a MHC-I-restricted cellular immunologic response to survivin vaccines. To study differences in immunogenicity between murine and human survivin proteins, we vaccinated C57BL/6 mice with bone marrow dendritic cells (BMDC) transfected with expression vectors containing the murine and human survivin genes. Mice vaccinated with BMDCs expressing a truncated human survivin protein developed cytotoxic T lymphocyte to subcutaneous GL261 glioma cells and exhibited prolonged tumor-free survival compared to mice vaccinated with BMDCs transfected with vector alone (P<0.01). While mice challenged with intracerebral GL261 cells had increased survival, no cures were observed. In contrast, vaccinated mice that fully resisted subcutaneous tumor challenge were rendered resistant to intracerebral GL261 re-challenge. BMDCs transfected with the full-length human survivin molecule were significantly more effective at prolonging survival than BMDCs expressing the full-length murine survivin gene (P=0.0175). Therefore, xenogeneic differences between human and murine sequences might be exploited to develop more immunogenic tumor vaccines.
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Affiliation(s)
- Michael J Ciesielski
- Departments of Neurosurgery and Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA.
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Sasaki K, Doh-ura K, Ironside J, Mabbott N, Iwaki T. Clusterin expression in follicular dendritic cells associated with prion protein accumulation. J Pathol 2006; 209:484-91. [PMID: 16767691 DOI: 10.1002/path.2009] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Peripheral accumulation of abnormal prion protein (PrP) in variant Creutzfeldt-Jakob disease and some animal models of transmissible spongiform encephalopathies (TSEs) may occur in the lymphoreticular system. Within the lymphoid tissues, abnormal PrP accumulation occurs on follicular dendritic cells (FDCs). Clusterin (apolipoprotein J) has been recognized as one of the molecules associated with PrP in TSEs, and clusterin expression is increased in the central nervous system where abnormal PrP deposition has occurred. We therefore examined peripheral clusterin expression in the context of PrP accumulation on FDCs in a range of human and experimental TSEs. PrP was detected immunohistochemically on tissue sections using a novel highly sensitive method involving detergent autoclaving pretreatment. A dendritic network pattern of clusterin immunoreactivity in lymphoid follicles was observed in association with the abnormal PrP on FDCs. The increased clusterin immunoreactivity appeared to correlate with the extent of PrP deposition, irrespective of the pathogen strains, host mouse strains or various immune modifications. The observed co-localization and correlative expression of these proteins suggested that clusterin might be directly associated with abnormal PrP. Indeed, clusterin immunoreactivity in association with PrP was retained after FDC depletion. Together these data suggest that clusterin may act as a chaperone-like molecule for PrP and play an important role in TSE pathogenesis.
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Affiliation(s)
- K Sasaki
- Department of Neuropathology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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Abstract
Multiple system atrophy (MSA) is a sporadic, adult-onset neurodegenerative disease, which is characterized by striatonigral degeneration, olivopontocerebellar atrophy, and preganglionic autonomic lesions in any combination. The histological hallmark is the presence of argyrophilic fibrillary inclusions in the oligodendrocytes, referred to as glial cytoplasmic inclusions (GCIs). Fibrillary inclusions are also found in the neuronal somata, axons, and nucleus. Neuronal cytoplasmic inclusions are frequently found in the pontine and inferior olivary nuclei. Since the discovery of alpha-synuclein as a major component of glial and neuronal inclusions in MSA, two neurodegenerative processes have been considered in this disease: one is due to the widespread occurrence of GCIs associated with oligodendroglia-myelin degeneration (oligodendrogliopathy) in the central nervous system, and the other is due to the filamentous aggregation of alpha-synuclein in the neurons in several brain regions. These two degenerative processes might synergistically cause neuronal depletion in MSA.
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Affiliation(s)
- Koichi Wakabayashi
- Department of Neuropathology, Institute of Brain Science, School of Medicine, Hirosaki University, Japan.
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Liu X, Chen N, Wang X, He Y, Chen X, Huang Y, Yin W, Zhou Q. Apoptosis and proliferation markers in diffusely infiltrating astrocytomas: profiling of 17 molecules. J Neuropathol Exp Neurol 2006; 65:905-13. [PMID: 16957584 DOI: 10.1097/01.jnen.0000235857.79502.c3] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Caspases and inhibitor of apoptosis proteins (IAPs) are antagonizing key apoptosis regulators. Limited studies of a few IAPs indicated their roles in astrocytomas. However, the overall expression status and significance of apoptosis regulators in astrocytomas is not clear. We examined the expression profile of the caspases (CASP3, 6, 7, 8, 9, 10, and 14), APAF1, SMAC, BCL2, the IAPs (BIRC5/survivin, CIAP1, CIAP2, XIAP, and LIVIN), and the proliferation markers Ki67 and PHH3 in 78 diffusely infiltrating astrocytomas and 24 normal brain samples by immunohistochemistry. Western blotting for major caspases and IAPs and reverse transcription-polymerase chain reaction analyses for IAPs were performed on a subset of 27 fresh samples. Our data showed BIRC5 nuclear labeling index (BIRC5-N) was the apoptosis marker most significantly different in World Health Organization grade II to IV astrocytomas and most strongly associated with proliferative activity. Expression level of other apoptosis-related proteins was modest or low in astrocytomas and did not correlate significantly with tumor grade or proliferation. Apoptosis regulators and proliferation markers were not detected in astrocytes of normal brain by immunostaining. This expression profile suggested involvement of apoptosis regulators in astrocytoma tumorigenesis, but tumor progression was more closely associated with proliferative advantages of which BIRC5 nuclear expression appeared to be a manifestation.
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Affiliation(s)
- Xinlian Liu
- Pathology Department, West China Hospital, West China Medical School, Sichuan University, Chengdu, China
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Fukuda S, Pelus LM. Survivin, a cancer target with an emerging role in normal adult tissues. Mol Cancer Ther 2006; 5:1087-98. [PMID: 16731740 DOI: 10.1158/1535-7163.mct-05-0375] [Citation(s) in RCA: 373] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Survivin, an inhibitor of apoptosis protein, is highly expressed in most cancers and associated with chemotherapy resistance, increased tumor recurrence, and shorter patient survival, making antisurvivin therapy an attractive cancer treatment strategy. However, growing evidence indicates that survivin is expressed in normal adult cells, particularly primitive hematopoietic cells, T lymphocytes, polymorphonuclear neutrophils, and vascular endothelial cells, and may regulate their proliferation or survival. In preclinical animal models, targeted antisurvivin therapies show efficacy without overt toxicity. However, consequences of prolonged survivin disruption in normal cells, particularly those associated with continuous renewal, have not been clearly determined. Understanding the role of survivin in normal versus malignant cells will be important in identifying strategies that maximally disrupt survivin in cancer cells with minimal effect on normal tissues. In this review, we summarize the prognostic relevance of survivin in cancer that justifies the pursuit of antisurvivin therapies and discuss differences in survivin expression between normal and cancer cells. We subsequently review expression of survivin in normal adult tissues and evaluate preclinical antisurvivin therapies reported to date in light of emerging roles for survivin in normal physiology, particularly hematopoiesis, angiogenesis, and immune function.
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Affiliation(s)
- Seiji Fukuda
- Walther Oncology Center, Indiana University School of Medicine, 950 West Walnut Street, Indianapolis, IN 46202, USA.
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