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Article ; Online: The targeted LHRH analog AEZS-108 alters expression of genes related to angiogenesis and development of metastasis in uveal melanoma.

Fodor, Klara / Dobos, Nikoletta / Schally, Andrew / Steiber, Zita / Olah, Gabor / Sipos, Eva / Szekvolgyi, Lorant / Halmos, Gabor

Oncotarget

2020 Volume 11, Issue 2, Page(s) 175–187

Abstract: Uveal melanoma (UM) is the most common malignant tumor of the eye. Recently, we have established that 46% of UM specimens express LHRH receptors. This finding supports the idea of a LHRH receptor-targeted therapy of UM patients. Cytotoxic analog of LHRH, ...

Abstract	Uveal melanoma (UM) is the most common malignant tumor of the eye. Recently, we have established that 46% of UM specimens express LHRH receptors. This finding supports the idea of a LHRH receptor-targeted therapy of UM patients. Cytotoxic analog of LHRH, AEZS-108 exhibits effective anti-cancer activity in LHRH-receptor positive cancers. AEZS-108 is a hybrid molecule, composed of a synthetic peptide carrier and the cytotoxic doxorubicin (DOX). In the present study, we investigated AEZS-108 induced cytotoxicity and the altered mRNA expression profile of regulatory factors related to angiogenesis and metastasis in LHRH receptor positive OCM3 cells. Our results show that AEZS-108 upregulates the expression of
Language	English
Publishing date	2020-01-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.27431
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Article ; Online: Expression of Luteinizing Hormone-Releasing Hormone (LHRH) and Type-I LHRH Receptor in Transitional Cell Carcinoma Type of Human Bladder Cancer.

Szabó, Zsuzsanna / Dezső, Balázs / Fodor, Klára / Szegedi, Krisztián / Flaskó, Tibor / Szabó, Erzsébet / Oláh, Gábor / Sipos, Éva / Dobos, Nikoletta / Gardi, János / Schally, Andrew V / Halmos, Gábor

Molecules (Basel, Switzerland)

2021 Volume 26, Issue 5

Abstract: Bladder cancer (BC) is the tenth most frequently detected cancer in both sexes. Type-I luteinizing hormone-releasing hormone (LHRH) receptor (LHRH-R-I) is expressed not only in the pituitary, but also in several types of cancer disease. There are few ... ...

Abstract	Bladder cancer (BC) is the tenth most frequently detected cancer in both sexes. Type-I luteinizing hormone-releasing hormone (LHRH) receptor (LHRH-R-I) is expressed not only in the pituitary, but also in several types of cancer disease. There are few data about LHRH-R-I expression in human BC. This study aimed to investigate the expression of LHRH and LHRH-R-I in the transitional cell carcinoma (TCC) type of human BC. RNA was extracted from 24 human bladder tumor specimens and three BC cell lines. RT-PCR was performed to detect mRNA for LHRH and LHRH-R-I. The protein of LHRH-R-I was further studied by immunohistochemistry (IHC), ligand competition assay, and Western Blot. PCR products of LHRH were found in 19 of 24 (79%) specimens and mRNA of LHRH-R-I was detected in 20 of 24 specimens (83%). Positive immunostaining for LHRH-R-I with different expression intensity was found in all samples examined, showing negative correlation with TCC grade. Radioligand binding studies also showed the presence of specific LHRH-R-I and high affinity binding of LHRH analogs. The high incidence of LHRH-R in BC suggests that it could serve as a molecular target for therapy of human BC with cytotoxic LHRH analogs or modern powerful antagonistic analogs of LHRH.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Carcinoma, Transitional Cell/drug therapy ; Carcinoma, Transitional Cell/epidemiology ; Carcinoma, Transitional Cell/genetics ; Carcinoma, Transitional Cell/pathology ; Cell Line, Tumor ; Doxorubicin/administration & dosage ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Gonadotropin-Releasing Hormone/genetics ; Humans ; Male ; Middle Aged ; RNA, Messenger/genetics ; Receptors, LHRH/genetics ; Urinary Bladder Neoplasms/drug therapy ; Urinary Bladder Neoplasms/epidemiology ; Urinary Bladder Neoplasms/genetics ; Urinary Bladder Neoplasms/pathology
Chemical Substances	RNA, Messenger ; Receptors, LHRH ; Gonadotropin-Releasing Hormone (33515-09-2) ; Doxorubicin (80168379AG)
Language	English
Publishing date	2021-02-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules26051253
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Article: Characterization of luteinizing hormone-releasing hormone receptor type I (LH-RH-I) as a potential molecular target in OCM-1 and OCM-3 human uveal melanoma cell lines.

Sipos, Eva / Dobos, Nikoletta / Rozsa, David / Fodor, Klara / Olah, Gabor / Szabo, Zsuzsanna / Szekvolgyi, Lorant / Schally, Andrew V / Halmos, Gabor

OncoTargets and therapy

2018 Volume 11, Page(s) 933–941

Abstract: Introduction: Uveal melanoma (UM) is the most common primary intraocular malignancy with very poor prognosis. Conventional chemotherapy only rarely prolongs the survival, therefore patients require novel treatment modalities. The discovery of specific ... ...

Abstract	Introduction: Uveal melanoma (UM) is the most common primary intraocular malignancy with very poor prognosis. Conventional chemotherapy only rarely prolongs the survival, therefore patients require novel treatment modalities. The discovery of specific receptors for hypothalamic hormones on cancer cells has led to the development of radiolabeled and cytotoxic hormone analogs. Materials and methods: In the present study, our aim was to investigate the expression of mRNA for receptors of luteinizing hormone-releasing hormone type I (LH-RH-I) and LH-RH ligand in OCM-1 and OCM-3 human uveal melanoma cell lines. The presence and binding characteristics of LH-RH-I receptor protein was further studied by Western blot, immunocytochemistry and ligand competition assay. The expression of mRNA and protein for LH-RH-I receptors has been also studied using tumor samples originating from nude mice xenografted with OCM-1 or OCM-3 cells. Results: The mRNA for LH-RH-I receptor has been detected in OCM-1 and OCM-3 cell lines and was found markedly higher in OCM-3 cells. The mRNA for LH-RH-I receptors was also observed in both UM xenograft models in vivo with higher levels in OCM-3. The presence of LH-RH-I receptor protein was found in both cell lines in vitro by immunocytochemistry and Western blot, and also in tumor tissue samples grown in nude mice by Western blot. Both human uveal melanoma models investigated showed specific high affinity receptors for LH-RH-I using ligand competition assay. The mRNA for LH-RH ligand has also been detected in OCM-1 and OCM-3 cell lines and cancer tissues. Conclusion: The demonstration of the expression of LH-RH-I receptors in OCM-1 and OCM-3 human UM cell lines suggests that they could serve as potential molecular target for therapy. Our findings support the development of new therapeutic approaches based on cytotoxic LH-RH analogs or modern powerful antagonistic analogs of LH-RH targeting LH-RH-I receptors in UM.
Language	English
Publishing date	2018-02-22
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2495130-4
ISSN	1178-6930
ISSN	1178-6930
DOI	10.2147/OTT.S148174
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Article ; Online: Somatostatin Receptors as Molecular Targets in Human Uveal Melanoma.

Harda, Kristof / Szabo, Zsuzsanna / Szabo, Erzsebet / Olah, Gabor / Fodor, Klara / Szasz, Csaba / Mehes, Gabor / Schally, Andrew V / Halmos, Gabor

Molecules (Basel, Switzerland)

2018 Volume 23, Issue 7

Abstract: Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, with an incidence of 4⁻5 cases per million. The prognosis of UM is very poor. In the present study, our aim was to investigate the expression of mRNA and protein for ... ...

Abstract	Uveal melanoma (UM) is the most common primary intraocular malignancy in adults, with an incidence of 4⁻5 cases per million. The prognosis of UM is very poor. In the present study, our aim was to investigate the expression of mRNA and protein for somatostatin receptor types-1, -2, -3, -4, -5 (SSTR-1⁻5) in human UM tissue samples and in OCM-1 and OCM-3 human UM cell lines by qRT-PCR, western blot and ligand competition assay. The mRNA for SSTR-2 showed markedly higher expression in UM tissues than SSTR-5. The presence of SSTRs was demonstrated in 70% of UM specimens using ligand competition assay and both human UM models displayed specific high affinity SSTRs. Among the five SSTRs, the mRNA investigated for SSTR-2 and SSTR-5 receptors was strongly expressed in both human UM cell lines, SSTR-5 showing the highest expression. The presence of the SSTR-2 and SSTR-5 receptor proteins was confirmed in both cell lines by western blot. In summary, the expression of somatostatin receptors in human UM specimens and in OCM-1 and OCM-3 human UM cell lines suggests that they could serve as a potential molecular target for therapy of UM using modern powerful cytotoxic SST analogs targeting SSTR-2 and SSTR-5 receptors.
MeSH term(s)	Aged ; Cell Line, Tumor ; Female ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Melanoma/drug therapy ; Melanoma/genetics ; Melanoma/pathology ; Molecular Targeted Therapy ; Receptors, Somatostatin/metabolism ; Uveal Neoplasms/drug therapy ; Uveal Neoplasms/genetics ; Uveal Neoplasms/pathology
Chemical Substances	Receptors, Somatostatin
Language	English
Publishing date	2018-06-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules23071535
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Article ; Online: Experimental therapy of doxorubicin resistant human uveal melanoma with targeted cytotoxic luteinizing hormone-releasing hormone analog (AN-152).

Oláh, Gábor / Dobos, Nikoletta / Vámosi, György / Szabó, Zsuzsanna / Sipos, Éva / Fodor, Klára / Harda, Kristóf / Schally, Andrew V / Halmos, Gábor

European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences

2018 Volume 123, Page(s) 371–376

Abstract: Background: Cytotoxic analogs of LHRH (luteinizing hormone-releasing hormone) can be successfully used for the treatment of hormone-dependent cancers such as prostatic, ovarian, endometrial, but our knowledge about their effect on hormone-independent ... ...

Abstract	Background: Cytotoxic analogs of LHRH (luteinizing hormone-releasing hormone) can be successfully used for the treatment of hormone-dependent cancers such as prostatic, ovarian, endometrial, but our knowledge about their effect on hormone-independent cancers such as human uveal melanoma (UM) is limited. Previously, we have demonstrated that 46% of UM express full-length LHRH receptors. This finding has led us to further examine the mechanism of action of LHRH receptor based targeted therapies in this malignancy. Aims: In the present study we investigated the cellular uptake of doxorubicin (DOX) and cytotoxic LHRH analog AN-152 (AEZS-108, zoptarelin doxorubicin) on human UM cell lines (OCM3) and its DOX resistant form OCM3 Results: We were able to establish a new, stable and DOX resistant human UM cell line OCM3 Conclusions: Our results suggest that the antiproliferative effect of AN-152 can be detected even if only LHRH receptor isoforms are expressed. Our study also demonstrates the LHRH receptor-mediated uptake of AN-152 in DOX resistant OCM3
MeSH term(s)	Antineoplastic Agents/metabolism ; Antineoplastic Agents/pharmacology ; Biological Transport ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Doxorubicin/analogs & derivatives ; Doxorubicin/metabolism ; Doxorubicin/pharmacology ; Drug Resistance, Neoplasm ; Gonadotropin-Releasing Hormone/agonists ; Gonadotropin-Releasing Hormone/analogs & derivatives ; Gonadotropin-Releasing Hormone/genetics ; Gonadotropin-Releasing Hormone/metabolism ; Gonadotropin-Releasing Hormone/pharmacology ; Humans ; Melanoma/drug therapy ; Melanoma/genetics ; Melanoma/metabolism ; Melanoma/pathology ; Protein Isoforms ; Signal Transduction/drug effects ; Uveal Neoplasms/drug therapy ; Uveal Neoplasms/genetics ; Uveal Neoplasms/metabolism ; Uveal Neoplasms/pathology
Chemical Substances	Antineoplastic Agents ; Protein Isoforms ; LHRH, lysine(6)-doxorubicin (27844X2J29) ; Gonadotropin-Releasing Hormone (33515-09-2) ; Doxorubicin (80168379AG)
Language	English
Publishing date	2018-08-02
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1154366-8
ISSN	1879-0720 ; 0928-0987
ISSN (online)	1879-0720
ISSN	0928-0987
DOI	10.1016/j.ejps.2018.08.002
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Article: Correlation between the Expression of Angiogenic Factors and Stem Cell Markers in Human Uveal Melanoma.

Fodor, Klára / Sipos, Éva / Dobos, Nikoletta / Nagy, János / Steiber, Zita / Méhes, Gábor / Dull, Kata / Székvölgyi, Lóránt / Schally, Andrew V / Halmos, Gábor

Life (Basel, Switzerland)

2020 Volume 10, Issue 12

Abstract: Uveal melanoma (UM) is the most common malignant tumor of the eye with extremely high metastatic potential. UM tumor cells can disseminate only hematogenously, thus, angiogenic signals have a particular role in the prognosis of the disease. Although the ... ...

Abstract	Uveal melanoma (UM) is the most common malignant tumor of the eye with extremely high metastatic potential. UM tumor cells can disseminate only hematogenously, thus, angiogenic signals have a particular role in the prognosis of the disease. Although the presence of cancer stem cells (CSCs) in densely vascularized UMs has been reported previously, their role in the process of hematogenous spread of UM has not been studied. In this study, we investigated the regulation of angiogenesis in UM in correlation with the presence of CSCs. Seventy UM samples were collected to analyze the expression of CSC markers and angiogenic factors. The expression of CSC markers was studied by RT-PCR, Western blotting techniques and IHC-TMA technique. RT-PCR showed high expression of CSC markers, particularly nestin, FZD6 and SOX10 and somewhat lower expression of NGFR. The protein expression of FZD6, HIF-1α and VEGFA was further evaluated in 52 UM samples by the IHC-TMA technique. We report here for the first time a significant correlation between FZD6 and VEGFA expression in UM samples. The observed correlation between FZD6 and VEGFA suggests the presence of CSCs in UM that are associated with the vascularization process.
Language	English
Publishing date	2020-11-25
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662250-6
ISSN	2075-1729
ISSN	2075-1729
DOI	10.3390/life10120310
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Article: Az Alzheimer-kór citoszkeletális változásai: a terápiás remény "váza"?

Fodor, Klára Eszter / Pákáski, Magdolna / Santha, Petra / Janka, Zoltán / Kálmán, János

Neuropsychopharmacologia Hungarica : a Magyar Pszichofarmakologiai Egyesulet lapja = official journal of the Hungarian Association of Psychopharmacology

2011 Volume 13, Issue 3, Page(s) 163–171

Abstract: Damage to and functional alteration of structures responsible for synaptic plasticity correlate with memory loss and cognitive decline in Alzheimer's disease. The results of recent research in the pathomechanism of Alzheimer's disease emphasize the ... ...

Title translation	Cytoskeletal alterations in Alzheimer's disease: the "skeleton" of therapeutic hope?.
Abstract	Damage to and functional alteration of structures responsible for synaptic plasticity correlate with memory loss and cognitive decline in Alzheimer's disease. The results of recent research in the pathomechanism of Alzheimer's disease emphasize the significance of cytoskeletal changes. The changes in actin dynamics and its regulation by actin-binding proteins have been proven in Alzheimer's disease, which may have a key role in the conformation and alteration of synapses and dendritic spines. The most important proteins in the regulation of actin dynamics are ADF/cofilin, kinases and drebrin. In this review, we summarize the physiological functions and complex regulation of these cytoskeletal proteins and their alterations in Alzheimer's disease. Additionally, the effects of some psychopharmacons on the actin cytoskeleton and cytoskeletal changes induced by stress are also summarized.
MeSH term(s)	Actin Depolymerizing Factors/metabolism ; Actins/metabolism ; Alzheimer Disease/drug therapy ; Alzheimer Disease/metabolism ; Alzheimer Disease/pathology ; Alzheimer Disease/physiopathology ; Amyloid/metabolism ; Cognition ; Cognition Disorders/metabolism ; Cognition Disorders/pathology ; Cytoskeleton/metabolism ; Cytoskeleton/pathology ; Dendritic Cells/metabolism ; Humans ; Neuronal Plasticity ; Neuropeptides/metabolism ; Phosphotransferases/metabolism ; Profilins/metabolism ; Synapses/metabolism
Chemical Substances	Actin Depolymerizing Factors ; Actins ; Amyloid ; Neuropeptides ; Profilins ; drebrins ; Phosphotransferases (EC 2.7.-)
Language	Hungarian
Publishing date	2011-08-11
Publishing country	Hungary
Document type	English Abstract ; Journal Article ; Review
ISSN	1419-8711
ISSN	1419-8711
DOI	10.5706/nph201109005
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Article ; Online: Concurrence of chromosome 3 and 4 aberrations in human uveal melanoma.

Sipos, Eva / Hegyi, Kata / Treszl, Andrea / Steiber, Zita / Mehes, Gabor / Dobos, Nikoletta / Fodor, Klara / Olah, Gabor / Szekvolgyi, Lorant / Schally, Andrew V / Halmos, Gabor

Oncology reports

2017 Volume 37, Issue 4, Page(s) 1927–1934

Abstract: Uveal melanoma (UM) is the most common primary intraocular malignancy with a very poor prognosis. The most frequent chromosome aberration in UM is the monosomy of chromosome 3. Previously, we demonstrated that ~50% of UMs express type-I receptor for ... ...

Abstract	Uveal melanoma (UM) is the most common primary intraocular malignancy with a very poor prognosis. The most frequent chromosome aberration in UM is the monosomy of chromosome 3. Previously, we demonstrated that ~50% of UMs express type-I receptor for luteinizing hormone‑releasing hormone (LH-RH-R). The gene encoding LH-RH-R is located in chromosome 4 (location: 4q21.2); however, the occurrence of numerical aberrations of chromosome 4 have never been studied in UM. In the present study, we investigated the abnormalities of chromosome 3 and 4, and the possible correlation between them, as well as with LH-RH-R expression. Forty-six specimens of UM were obtained after enucleation. Numerical aberrations of chromosome 3 and 4 were studied by fluorescence in situ hybridization (FISH). Chromosome 4 was detected in normal biparental disomy only in 14 (30%) samples; however, 32 cases (70%) showed more than 2 signals/nucleus. Monosomy of chromosome 3 could be found in 16 (35%) samples. In 6 specimens (13%), more than 2 copies of chromosome 3 were found, while normal biparental disomy was detected in 24 (52%) samples. Statistical analysis indicated a statistically significant (p<0.05) correlation between the copy number of chromosome 3 and 4. Moreover, moderate difference was revealed in the survival rate of the UM patients with various pathological profiles. No correlation was found between chromosome aberrations and LH-RH-R expression. Our results clearly demonstrate abnormalities in chromosome 3 and 4 and the incidence of the monosomy of chromosome 3 in human UM. In summary, our results provide new incite concerning the genetic background of this tumor. Our findings could contribute to a more precise determination of the prognosis of human UM and to the development of new therapeutic approaches to this malignancy.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Chromosome Aberrations ; Chromosomes, Human, Pair 3/genetics ; Chromosomes, Human, Pair 4/genetics ; Female ; Humans ; In Situ Hybridization, Fluorescence ; Male ; Melanoma/genetics ; Middle Aged ; Prognosis ; Receptors, LHRH ; Survival Analysis ; Uveal Neoplasms/genetics
Chemical Substances	Receptors, LHRH
Language	English
Publishing date	2017-03-08
Publishing country	Greece
Document type	Journal Article
ZDB-ID	1222484-4
ISSN	1791-2431 ; 1021-335X
ISSN (online)	1791-2431
ISSN	1021-335X
DOI	10.3892/or.2017.5496
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Zs.A 4213: Show issues

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Article ; Online: Substantial expression of luteinizing hormone-releasing hormone (LHRH) receptor type I in human uveal melanoma.

Treszl, Andrea / Steiber, Zita / Schally, Andrew V / Block, Norman L / Dezso, Balazs / Olah, Gabor / Rozsa, Bernadett / Fodor, Klara / Buglyo, Armin / Gardi, Janos / Berta, Andras / Halmos, Gabor

Oncotarget

2013 Volume 4, Issue 10, Page(s) 1721–1728

Abstract: Uveal melanoma is the most common primary intraocular malignancy in adults, with a very high mortality rate due to frequent liver metastases. Consequently, the therapy of uveal melanoma remains a major clinical challenge and new treatment approaches are ... ...

Abstract	Uveal melanoma is the most common primary intraocular malignancy in adults, with a very high mortality rate due to frequent liver metastases. Consequently, the therapy of uveal melanoma remains a major clinical challenge and new treatment approaches are needed. For improving diagnosis and designing a rational and effective therapy, it is essential to elucidate molecular characteristics of this malignancy. The aim of this study therefore was to evaluate as a potential therapeutic target the expression of luteinizing hormone-releasing hormone (LHRH) receptor in human uveal melanoma. The expression of LHRH ligand and LHRH receptor transcript forms was studied in 39 human uveal melanoma specimens by RT-PCR using gene specific primers. The binding charachteristics of receptors for LHRH on 10 samples were determined by ligand competition assays. The presence of LHRH receptor protein was further evaluated by immunohistochemistry. The expression of mRNA for type I LHRH receptor was detected in 18 of 39 (46%) of tissue specimens. mRNA for LHRH-I ligand could be detected in 27 of 39 (69%) of the samples. Seven of 10 samples investigated showed high affinity LHRH-I receptors. The specific presence of full length LHRH receptor protein was further confirmed by immunohistochemistry. A high percentage of uveal melanomas express mRNA and protein for type-I LHRH receptors. Our results support the merit of further investigation of LHRH receptors in human ophthalmological tumors. Since diverse analogs of LHRH are in clinical trials or are already used for the treatment of various cancers, theseanalogs could be considered for the LHRH receptor-based treatment of uveal melanoma.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Immunohistochemistry ; Male ; Melanoma/genetics ; Melanoma/metabolism ; Middle Aged ; RNA, Messenger/biosynthesis ; RNA, Messenger/genetics ; Receptors, LHRH/biosynthesis ; Receptors, LHRH/genetics ; Uveal Neoplasms/genetics ; Uveal Neoplasms/metabolism
Chemical Substances	RNA, Messenger ; Receptors, LHRH
Language	English
Publishing date	2013-09-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.1379
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