@article{SongJiaZhangetal.2016, author = {Song, Ning-Ning and Jia, Yun-Fang and Zhang, Lei and Zhang, Qiong and Huang, Ying and Liu, Xiao-Zhen and Hu, Ling and Lan, Wei and Chen, Ling and Lesch, Klaus-Peter and Chen, Xiaoyan and Xu, Lin and Ding, Yu-Qiang}, title = {Reducing central serotonin in adulthood promotes hippocampal neurogenesis}, series = {Scientific Reports}, volume = {6}, journal = {Scientific Reports}, number = {20338}, doi = {10.1038/srep20338}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-168004}, year = {2016}, abstract = {Chronic administration of selective serotonin reuptake inhibitors (SSRIs), which up-regulates central serotonin (5-HT) system function, enhances adult hippocampal neurogenesis. However, the relationship between central 5-HT system and adult neurogenesis has not fully been understood. Here, we report that lowering 5-HT level in adulthood is also able to enhance adult hippocampal neurogenesis. We used tamoxifen (TM)-induced Cre in Pet1-CreER\(^{T2}\) mice to either deplete central serotonergic (5-HTergic) neurons or inactivate 5-HT synthesis in adulthood and explore the role of central 5-HT in adult hippocampal neurogenesis. A dramatic increase in hippocampal neurogenesis is present in these two central 5-HT-deficient mice and it is largely prevented by administration of agonist for 5-HTR2c receptor. In addition, the survival of new-born neurons in the hippocampus is enhanced. Furthermore, the adult 5-HT-deficient mice showed reduced depression-like behaviors but enhanced contextual fear memory. These findings demonstrate that lowering central 5-HT function in adulthood can also enhance adult hippocampal neurogenesis, thus revealing a new aspect of central 5-HT in regulating adult neurogenesis.}, language = {en} } @article{ChenYuZhangetal.2011, author = {Chen, Nanhai G. and Yu, Yong A. and Zhang, Qian and Szalay, Aladar A.}, title = {Replication efficiency of oncolytic vaccinia virus in cell cultures prognosticates the virulence and antitumor efficacy in mice}, series = {Journal of Translational Medicine}, volume = {9}, journal = {Journal of Translational Medicine}, number = {164}, doi = {10.1186/1479-5876-9-164}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-142268}, pages = {1-11}, year = {2011}, abstract = {Background: We have shown that insertion of the three vaccinia virus (VACV) promoter-driven foreign gene expression cassettes encoding Renilla luciferase-Aequorea GFP fusion protein, beta-galactosidase, and beta-glucuronidase into the F14.5L, J2R, and A56R loci of the VACV LIVP genome, respectively, results in a highly attenuated mutant strain GLV 1h68. This strain shows tumor specific replication and is capable of eradicating tumors with little or no virulence in mice. This study aimed to distinguish the contribution of added VACV promoter-driven transcriptional units as inserts from the effects of insertional inactivation of three viral genes, and to determine the correlation between replication efficiency of oncolytic vaccinia virus in cell cultures and the virulence and antitumor efficacy in mice Methods: A series of recombinant VACV strains was generated by replacing one, two, or all three of the expression cassettes in GLV 1h68 with short non coding DNA sequences. The replication efficiency and tumor cell killing capacity of these newly generated VACV strains were compared with those of the parent virus GLV-1h68 in cell cultures. The virus replication efficiency in tumors and antitumor efficacy as well as the virulence were evaluated in nu/nu (nude) mice bearing human breast tumor xenografts. Results: we found that virus replication efficiency increased with removal of each of the expression cassettes. The increase in virus replication efficiency was proportionate to the strength of removed VACV promoters linked to foreign genes. The replication efficiency of the new VACV strains paralleled their cytotoxicity in cell cultures. The increased replication efficiency in tumor xenografts resulted in enhanced antitumor efficacy in nude mice. Similarly, the enhanced virus replication efficiency was indicative of increased virulence in nude mice. Conclusions: These data demonstrated that insertion of VACV promoter-driven transcriptional units into the viral genome for the purpose of insertional mutagenesis did modulate the efficiency of virus replication together with antitumor efficacy as well as virulence. Replication efficiency of oncolytic VACV in cell cultures can predict the virulence and therapeutic efficacy in nude mice. These findings may be essential for rational design of safe and potent VACV strains for vaccination and virotherapy of cancer in humans and animals.}, language = {en} } @article{HaddadChenZhangetal.2011, author = {Haddad, Dana and Chen, Nanhai G. and Zhang, Qian and Chen, Chun-Hao and Yu, Yong A. and Gonzalez, Lorena and Carpenter, Susanne G. and Carson, Joshua and Au, Joyce and Mittra, Arjun and Gonen, Mithat and Zanzonico, Pat B. and Fong, Yuman and Szalay, Aladar A.}, title = {Insertion of the human sodium iodide symporter to facilitate deep tissue imaging does not alter oncolytic or replication capability of a novel vaccinia virus}, series = {Journal of Translational Medicine}, volume = {9}, journal = {Journal of Translational Medicine}, number = {36}, doi = {10.1186/1479-5876-9-36}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-140847}, pages = {1-14}, year = {2011}, abstract = {Introduction: Oncolytic viruses show promise for treating cancer. However, to assess therapeutic efficacy and potential toxicity, a noninvasive imaging modality is needed. This study aimed to determine if insertion of the human sodium iodide symporter (hNIS) cDNA as a marker for non-invasive imaging of virotherapy alters the replication and oncolytic capability of a novel vaccinia virus, GLV-1h153. Methods: GLV-1h153 was modified from parental vaccinia virus GLV-1h68 to carry hNIS via homologous recombination. GLV-1h153 was tested against human pancreatic cancer cell line PANC-1 for replication via viral plaque assays and flow cytometry. Expression and transportation of hNIS in infected cells was evaluated using Westernblot and immunofluorescence. Intracellular uptake of radioiodide was assessed using radiouptake assays. Viral cytotoxicity and tumor regression of treated PANC-1tumor xenografts in nude mice was also determined. Finally, tumor radiouptake in xenografts was assessed via positron emission tomography (PET) utilizing carrier-free (124)I radiotracer. Results: GLV-1h153 infected, replicated within, and killed PANC-1 cells as efficiently as GLV-1h68. GLV-1h153 provided dose-dependent levels of hNIS expression in infected cells. Immunofluorescence detected transport of the protein to the cell membrane prior to cell lysis, enhancing hNIS-specific radiouptake (P < 0.001). In vivo, GLV-1h153 was as safe and effective as GLV-1h68 in regressing pancreatic cancer xenografts (P < 0.001). Finally, intratumoral injection of GLV-1h153 facilitated imaging of virus replication in tumors via (124)I-PET. Conclusion: Insertion of the hNIS gene does not hinder replication or oncolytic capability of GLV-1h153, rendering this novel virus a promising new candidate for the noninvasive imaging and tracking of oncolytic viral therapy.}, language = {en} } @article{SturmHessWeibeletal.2012, author = {Sturm, Julia B. and Hess, Michael and Weibel, Stephanie and Chen, Nanhei G. and Yu, Yong A. and Zhang, Quian and Donat, Ulrike and Reiss, Cora and Gambaryan, Stepan and Krohne, Georg and Stritzker, Jochen and Szalay, Aladar A.}, title = {Functional hyper-IL-6 from vaccinia virus-colonized tumors triggers platelet formation and helps to alleviate toxicity of mitomycin C enhanced virus therapy}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75224}, year = {2012}, abstract = {Background: Combination of oncolytic vaccinia virus therapy with conventional chemotherapy has shown promise for tumor therapy. However, side effects of chemotherapy including thrombocytopenia, still remain problematic. Methods: Here, we describe a novel approach to optimize combination therapy of oncolytic virus and chemotherapy utilizing virus-encoding hyper-IL-6, GLV-1h90, to reduce chemotherapy-associated side effects. Results: We showed that the hyper-IL-6 cytokine was successfully produced by GLV-1h90 and was functional both in cell culture as well as in tumor-bearing animals, in which the cytokine-producing vaccinia virus strain was well tolerated. When combined with the chemotherapeutic mitomycin C, the anti-tumor effect of the oncolytic virotherapy was significantly enhanced. Moreover, hyper-IL-6 expression greatly reduced the time interval during which the mice suffered from chemotherapy-induced thrombocytopenia. Conclusion: Therefore, future clinical application would benefit from careful investigation of additional cytokine treatment to reduce chemotherapy-induced side effects.}, subject = {Biologie}, language = {en} } @article{AdelfingerGentschevdeGuibertetal.2014, author = {Adelfinger, Marion and Gentschev, Ivaylo and de Guibert, Julio Grimm and Weibel, Stephanie and Langbein-Laugwitz, Johanna and H{\"a}rtl, Barbara and Escobar, Hugo Murua and Nolte, Ingo and Chen, Nanhai G. and Aguilar, Richard J. and Yu, Yong A. and Zhang, Qian and Frentzen, Alexa and Szalay, Aladar A.}, title = {Evaluation of a New Recombinant Oncolytic Vaccinia Virus Strain GLV-5b451 for Feline Mammary Carcinoma Therapy}, series = {PLoS ONE}, volume = {9}, journal = {PLoS ONE}, number = {8}, doi = {10.1371/journal.pone.0104337}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-119387}, pages = {e104337}, year = {2014}, abstract = {Virotherapy on the basis of oncolytic vaccinia virus (VACV) infection is a promising approach for cancer therapy. In this study we describe the establishment of a new preclinical model of feline mammary carcinoma (FMC) using a recently established cancer cell line, DT09/06. In addition, we evaluated a recombinant vaccinia virus strain, GLV-5b451, expressing the anti-vascular endothelial growth factor (VEGF) single-chain antibody (scAb) GLAF-2 as an oncolytic agent against FMC. Cell culture data demonstrate that GLV-5b451 virus efficiently infected, replicated in and destroyed DT09/06 cancer cells. In the selected xenografts of FMC, a single systemic administration of GLV-5b451 led to significant inhibition of tumor growth in comparison to untreated tumor-bearing mice. Furthermore, tumor-specific virus infection led to overproduction of functional scAb GLAF-2, which caused drastic reduction of intratumoral VEGF levels and inhibition of angiogenesis. In summary, here we have shown, for the first time, that the vaccinia virus strains and especially GLV-5b451 have great potential for effective treatment of FMC in animal model.}, language = {en} } @article{JinAllisonKaufmannetal.2012, author = {Jin, Jing and Allison, Brendan Z. and Kaufmann, Tobias and K{\"u}bler, Andrea and Zhang, Yu and Wang, Xingyu and Cichocki, Andrzej}, title = {The Changing Face of P300 BCIs: A Comparison of Stimulus Changes in a P300 BCI Involving Faces, Emotion, and Movement}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {11}, doi = {10.1371/journal.pone.0049688}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-134173}, pages = {e49688}, year = {2012}, abstract = {Background: One of the most common types of brain-computer interfaces (BCIs) is called a P300 BCI, since it relies on the P300 and other event-related potentials (ERPs). In the canonical P300 BCI approach, items on a monitor flash briefly to elicit the necessary ERPs. Very recent work has shown that this approach may yield lower performance than alternate paradigms in which the items do not flash but instead change in other ways, such as moving, changing colour or changing to characters overlaid with faces. Methodology/Principal Findings: The present study sought to extend this research direction by parametrically comparing different ways to change items in a P300 BCI. Healthy subjects used a P300 BCI across six different conditions. Three conditions were similar to our prior work, providing the first direct comparison of characters flashing, moving, and changing to faces. Three new conditions also explored facial motion and emotional expression. The six conditions were compared across objective measures such as classification accuracy and bit rate as well as subjective measures such as perceived difficulty. In line with recent studies, our results indicated that the character flash condition resulted in the lowest accuracy and bit rate. All four face conditions (mean accuracy >91\%) yielded significantly better performance than the flash condition (mean accuracy = 75\%). Conclusions/Significance: Objective results reaffirmed that the face paradigm is superior to the canonical flash approach that has dominated P300 BCIs for over 20 years. The subjective reports indicated that the conditions that yielded better performance were not considered especially burdensome. Therefore, although further work is needed to identify which face paradigm is best, it is clear that the canonical flash approach should be replaced with a face paradigm when aiming at increasing bit rate. However, the face paradigm has to be further explored with practical applications particularly with locked-in patients.}, language = {en} } @article{SongXiuHuangetal.2011, author = {Song, Ning-Ning and Xiu, Jian-Bo and Huang, Ying and Chen, Jia-Yin and Zhang, Lei and Gutknecht, Lise and Lesch, Klaus Peter and Li, He and Ding, Yu-Qiang}, title = {Adult Raphe-Specific Deletion of Lmx1b Leads to Central Serotonin Deficiency}, series = {PLoS ONE}, volume = {6}, journal = {PLoS ONE}, number = {1}, doi = {10.1371/journal.pone.0015998}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-133581}, pages = {e15998}, year = {2011}, abstract = {The transcription factor Lmx1b is essential for the differentiation and survival of central serotonergic (5-HTergic) neurons during embryonic development. However, the role of Lmx1b in adult 5-HTergic neurons is unknown. We used an inducible Cre-LoxP system to selectively inactivate Lmx1b expression in the raphe nuclei of adult mice. Pet1-CreER(T2) mice were generated and crossed with Lmx1b(flox/flox) mice to obtain Pet1-CreER(T2); Lmx1b(flox/flox) mice (which termed as Lmx1b iCKO). After administration of tamoxifen, the level of 5-HT in the brain of Lmx1b iCKO mice was reduced to 60\% of that in control mice, and the expression of tryptophan hydroxylase 2 (Tph2), serotonin transporter (Sert) and vesicular monoamine transporter 2 (Vmat2) was greatly down-regulated. On the other hand, the expression of dopamine and norepinephrine as well as aromatic L-amino acid decarboxylase (Aadc) and Pet1 was unchanged. Our results reveal that Lmx1b is required for the biosynthesis of 5-HT in adult mouse brain, and it may be involved in maintaining normal functions of central 5-HTergic neurons by regulating the expression of Tph2, Sert and Vmat2.}, language = {en} } @article{GentschevMuellerAdelfingeretal.2011, author = {Gentschev, Ivaylo and M{\"u}ller, Meike and Adelfinger, Marion and Weibel, Stephanie and Grummt, Friedrich and Zimmermann, Martina and Bitzer, Michael and Heisig, Martin and Zhang, Qian and Yu, Yong A. and Chen, Nanhai G. and Stritzker, Jochen and Lauer, Ulrich M. and Szalay, Aladar A.}, title = {Efficient Colonization and Therapy of Human Hepatocellular Carcinoma (HCC) Using the Oncolytic Vaccinia Virus Strain GLV-1h68}, series = {PLOS ONE}, volume = {6}, journal = {PLOS ONE}, number = {7}, doi = {10.1371/journal.pone.0022069}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-135319}, pages = {e22069}, year = {2011}, abstract = {Virotherapy using oncolytic vaccinia virus strains is one of the most promising new strategies for cancer therapy. In this study, we analyzed for the first time the therapeutic efficacy of the oncolytic vaccinia virus GLV-1h68 in two human hepatocellular carcinoma cell lines HuH7 and PLC/PRF/5 (PLC) in cell culture and in tumor xenograft models. By viral proliferation assays and cell survival tests, we demonstrated that GLV-1h68 efficiently colonized, replicated in, and did lyse these cancer cells in culture. Experiments with HuH7 and PLC xenografts have revealed that a single intravenous injection (i.v.) of mice with GLV-1h68 resulted in a significant reduction of primary tumor sizes compared to uninjected controls. In addition, replication of GLV-1h68 in tumor cells led to strong inflammatory and oncolytic effects resulting in intense infiltration of MHC class II-positive cells like neutrophils, macrophages, B cells and dendritic cells and in up-regulation of 13 pro-inflammatory cytokines. Furthermore, GLV-1h68 infection of PLC tumors inhibited the formation of hemorrhagic structures which occur naturally in PLC tumors. Interestingly, we found a strongly reduced vascular density in infected PLC tumors only, but not in the non-hemorrhagic HuH7 tumor model. These data demonstrate that the GLV-1h68 vaccinia virus may have an enormous potential for treatment of human hepatocellular carcinoma in man.}, language = {en} } @article{WangChenMinevetal.2013, author = {Wang, Huiqiang and Chen, Nanhai G. and Minev, Boris R. and Zimmermann, Martina and Aguilar, Richard J. and Zhang, Qian and Sturm, Julia B. and Fend, Falko and Yu, Yong A. and Cappello, Joseph and Lauer, Ulrich M. and Szalay, Aladar A.}, title = {Optical Detection and Virotherapy of Live Metastatic Tumor Cells in Body Fluids with Vaccinia Strains}, series = {PLoS ONE}, volume = {8}, journal = {PLoS ONE}, number = {9}, doi = {10.1371/journal.pone.0071105}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-130059}, pages = {e71105}, year = {2013}, abstract = {Metastatic tumor cells in body fluids are important targets for treatment, and critical surrogate markers for evaluating cancer prognosis and therapeutic response. Here we report, for the first time, that live metastatic tumor cells in blood samples from mice bearing human tumor xenografts and in blood and cerebrospinal fluid samples from patients with cancer were successfully detected using a tumor cell-specific recombinant vaccinia virus (VACV). In contrast to the FDA-approved CellSearch system, VACV detects circulating tumor cells (CTCs) in a cancer biomarker-independent manner, thus, free of any bias related to the use of antibodies, and can be potentially a universal system for detection of live CTCs of any tumor type, not limited to CTCs of epithelial origin. Furthermore, we demonstrate for the first time that VACV was effective in preventing and reducing circulating tumor cells in mice bearing human tumor xenografts. Importantly, a single intra-peritoneal delivery of VACV resulted in a dramatic decline in the number of tumor cells in the ascitic fluid from a patient with gastric cancer. Taken together, these results suggest VACV to be a useful tool for quantitative detection of live tumor cells in liquid biopsies as well as a potentially effective treatment for reducing or eliminating live tumor cells in body fluids of patients with metastatic disease.}, language = {en} } @article{GentschevAdelfingerJosupeitetal.2012, author = {Gentschev, Ivaylo and Adelfinger, Marion and Josupeit, Rafael and Rudolph, Stephan and Ehrig, Klaas and Donat, Ulrike and Weibel, Stephanie and Chen, Nanhai G. and Yu, Yong A. and Zhang, Qian and Heisig, Martin and Thamm, Douglas and Stritzker, Jochen and MacNeill, Amy and Szalay, Aladar A.}, title = {Preclinical Evaluation of Oncolytic Vaccinia Virus for Therapy of Canine Soft Tissue Sarcoma}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {5}, doi = {10.1371/journal.pone.0037239}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-129998}, year = {2012}, abstract = {Virotherapy using oncolytic vaccinia virus (VACV) strains is one promising new strategy for canine cancer therapy. In this study we describe the establishment of an in vivo model of canine soft tissue sarcoma (CSTS) using the new isolated cell line STSA-1 and the analysis of the virus-mediated oncolytic and immunological effects of two different Lister VACV LIVP1.1.1 and GLV-1h68 strains against CSTS. Cell culture data demonstrated that both tested VACV strains efficiently infected and destroyed cells of the canine soft tissue sarcoma line STSA-1. In addition, in our new canine sarcoma tumor xenograft mouse model, systemic administration of LIVP1.1.1 or GLV-1h68 viruses led to significant inhibition of tumor growth compared to control mice. Furthermore, LIVP1.1.1 mediated therapy resulted in almost complete tumor regression and resulted in long-term survival of sarcoma-bearing mice. The replication of the tested VACV strains in tumor tissues led to strong oncolytic effects accompanied by an intense intratumoral infiltration of host immune cells, mainly neutrophils. These findings suggest that the direct viral oncolysis of tumor cells and the virus-dependent activation of tumor-associated host immune cells could be crucial parts of anti-tumor mechanism in STSA-1 xenografts. In summary, the data showed that both tested vaccinia virus strains and especially LIVP1.1.1 have great potential for effective treatment of CSTS.}, language = {en} }