@article{gostner_update_2012,

title = {An update on the strategies in multicomponent activity monitoring within the phytopharmaceutical field.},

author = {Johanna M. Gostner and Oliver A. Wrulich and Marcel Jenny and Dietmar Fuchs and Florian Ueberall},

doi = {10.1186/1472-6882-12-18},

issn = {1472-6882},

year  = {2012},

date = {2012-03-01},

journal = {BMC complementary and alternative medicine},

volume = {12},

pages = {18},

abstract = {BACKGROUND: To-date modern drug research has focused on the discovery and synthesis of single active substances. However, multicomponent preparations are gaining increasing importance in the phytopharmaceutical field by demonstrating beneficial properties with respect to efficacy and toxicity. DISCUSSION: In contrast to single drug combinations, a botanical multicomponent therapeutic possesses a complex repertoire of chemicals that belong to a variety of substance classes. This may explain the frequently observed pleiotropic bioactivity spectra of these compounds, which may also suggest that they possess novel therapeutic opportunities. Interestingly, considerable bioactivity properties are exhibited not only by remedies that contain high doses of phytochemicals with prominent pharmaceutical efficacy, but also preparations that lack a sole active principle component. Despite that each individual substance within these multicomponents has a low molar fraction, the therapeutic activity of these substances is established via a potentialization of their effects through combined and simultaneous attacks on multiple molecular targets. Although beneficial properties may emerge from such a broad range of perturbations on cellular machinery, validation and/or prediction of their activity profiles is accompanied with a variety of difficulties in generic risk-benefit assessments. Thus, it is recommended that a comprehensive strategy is implemented to cover the entirety of multicomponent-multitarget effects, so as to address the limitations of conventional approaches. SUMMARY: An integration of standard toxicological methods with selected pathway-focused bioassays and unbiased data acquisition strategies (such as gene expression analysis) would be advantageous in building an interaction network model to consider all of the effects, whether they were intended or adverse reactions.},

note = {Place: England},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{gostner_antimalarial_2012,

title = {Antimalarial drug chloroquine counteracts activation of indoleamine (2,3)-dioxygenase activity in human PBMC.},

author = {Johanna M. Gostner and Sebastian Schröcksnadel and Kathrin Becker and Marcel Jenny and Harald Schennach and Florian Uberall and Dietmar Fuchs},

doi = {10.1016/j.fob.2012.08.004},

issn = {2211-5463},

year  = {2012},

date = {2012-01-01},

journal = {FEBS open bio},

volume = {2},

pages = {241–245},

abstract = {Antimalarial chloroquine is also used for the treatment of immune-mediated diseases. The interference of chloroquine with interferon-γ-induced tryptophan breakdown and neopterin production has been investigated in human peripheral blood mononuclear cells (PBMC) in vitro. Micromolar concentrations (2-50 μM) of chloroquine dose-dependently suppressed mitogen-induced tryptophan breakdown in PBMC but not in the myelomonocytic THP-1-Blue cell line, after 48 h of treatment. In stimulated PBMC, neopterin production was super-induced by 10 μM chloroquine, while it was significantly suppressed at a concentration of 50 μM. These anti-inflammatory effects may relate to the therapeutic benefit of chloroquine in inflammatory conditions and may widen the spectrum of its clinical applications.},

note = {Place: England},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{gostner_effects_2011,

title = {Effects of EpCAM overexpression on human breast cancer cell lines.},

author = {Johanna M. Gostner and Dominic Fong and Oliver A. Wrulich and Florian Lehne and Marion Zitt and Martin Hermann and Sylvia Krobitsch and Agnieszka Martowicz and Guenther Gastl and Gilbert Spizzo},

doi = {10.1186/1471-2407-11-45},

issn = {1471-2407},

year  = {2011},

date = {2011-01-01},

journal = {BMC cancer},

volume = {11},

pages = {45},

abstract = {BACKGROUND: Recently, EpCAM has attracted major interest as a target for antibody- and vaccine-based cancer immunotherapies. In breast cancer, the EpCAM antigen is overexpressed in 30-40% of all cases and this increased expression correlates with poor prognosis. The use of EpCAM-specific monoclonal antibodies is a promising treatment approach in these patients. METHODS: In order to explore molecular changes following EpCAM overexpression, we investigated changes of the transcriptome upon EpCAM gene expression in commercially available human breast cancer cells lines Hs578T and MDA-MB-231. To assess cell proliferation, a tetrazolium salt based assay was performed. A TCF/LEF Reporter Kit was used to measure the transcriptional activity of the Wnt/β-catenin pathway. To evaluate the accumulation of β-catenin in the nucleus, a subcellular fractionation assay was performed. RESULTS: For the first time we could show that expression profiling data of EpCAM transfected cell lines Hs578TEpCAM and MDA-MB-231EpCAM indicate an association of EpCAM overexpression with the downregulation of the Wnt signaling inhibitors SFRP1 and TCF7L2. Confirmation of increased Wnt signaling was provided by a TCF/LEF reporter kit and by the finding of the nuclear accumulation of ß-catenin for MDA-MB-231 EpCAM but not Hs578T EpCAM cells. In Hs578T cells, an increase of proliferation and chemosensitivity to Docetaxel was associated with EpCAM overexpression. CONCLUSIONS: These data show a cell type dependent modification of Wnt signaling components after EpCAM overexpression in breast cancer cell lines, which results in marginal functional changes. Further investigations on the interaction of EpCAM with SFRP1 and TCF7L2 and on additional factors, which may be causal for changes upon EpCAM overexpression, will help to characterize unique molecular properties of EpCAM-positive breast cancer cells.},

note = {Place: England},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{muhlmann_trop2_2009,

title = {TROP2 expression as prognostic marker for gastric carcinoma.},

author = {G. Mühlmann and G. Spizzo and J. Gostner and M. Zitt and H. Maier and P. Moser and G. Gastl and M. Zitt and H. M. Müller and R. Margreiter and D. Ofner and D. Fong},

doi = {10.1136/jcp.2008.060590},

issn = {1472-4146 0021-9746},

year  = {2009},

date = {2009-02-01},

journal = {Journal of clinical pathology},

volume = {62},

number = {2},

pages = {152–158},

abstract = {BACKGROUND: In gastric cancer the recurrence rate is unacceptably high, even after R0 resection and (neo)adjuvant chemotherapy. Therefore, there is an urgent need for identification of predictive and/or prognostic biomarkers to select high-risk patients who might benefit from additional therapies. Expression of TROP2 has been shown to be associated with tumour aggressiveness and poor prognosis in patients with various epithelial cancers. AIMS: To investigate TROP2 expression in gastric cancer and its correlation with clinicopathological features and disease outcome. METHODS: Expression of TROP2 was investigated by immunohistochemistry of tumour specimens from 104 patients who underwent resection for gastric cancer. Parameters found to be of prognostic significance in univariate analysis were verified in a multivariate Cox regression model. RESULTS: TROP2 was found to be overexpressed in 58 (56%) tumour samples. Significantly higher expression of TROP2 could be detected in intestinal-type carcinomas (p = 0.03). In intestinal-type gastric cancer, TROP2 overexpression was significantly correlated with shorter disease-free survival (DFS) (p = 0.03). Among the total group, TROP2 overexpression was predictive for poor disease-free (p<0.01) and overall (p = 0.03) survival in lymph node positive patients. Multivariate Cox regression analysis revealed TROP2 overexpression to be an independent prognostic marker for poor DFS in the subgroup of patients with intestinal-type gastric cancer irrespective of lymph node involvement. CONCLUSION: Results show that TROP2 is an independent prognostic marker for disease recurrence in intestinal type gastric cancer. Due to its wide distribution TROP2 may become an attractive therapeutic target in a subgroup of patients with gastric cancer.},

note = {Place: England},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{fong_high_2008,

title = {High expression of TROP2 correlates with poor prognosis in pancreatic cancer.},

author = {D. Fong and P. Moser and C. Krammel and J. M. Gostner and R. Margreiter and M. Mitterer and G. Gastl and G. Spizzo},

doi = {10.1038/sj.bjc.6604677},

issn = {1532-1827 0007-0920},

year  = {2008},

date = {2008-10-01},

journal = {British journal of cancer},

volume = {99},

number = {8},

pages = {1290–1295},

abstract = {Pancreatic cancer is one of the most devastating human malignancies. Despite considerable research efforts, it remains resistant to almost all available treatment regimens. The human trophoblast cell-surface antigen, TROP2, was found to be strongly expressed in a variety of human epithelial cancers, correlating with aggressiveness and poor prognosis. TROP2 antigen expression was investigated retrospectively by immunohistochemistry in paraffin-embedded primary tumour tissue samples from a series (n=197) of consecutive patients with pancreatic adenocarcinoma. Survival was calculated using Kaplan-Meier curves. Parameters found to be of prognostic significance in univariate analysis were verified in a multivariate Cox regression model. TROP2 overexpression was observed in 109 (55%) of 197 pancreatic cancer patients and was significantly associated with decreased overall survival (P<0.01). By univariate analysis, TROP2 overexpression was found to correlate with the presence of lymph node metastasis (P=0.04) and tumour grade (P=0.01). Furthermore, in the subgroup of patients treated surgically with curative intent, TROP2 overexpression significantly correlated with poor progression-free survival (P<0.01). Multivariate analyses revealed TROP2 to be an independent prognosticator. These findings suggest for the first time that TROP2 could be a novel prognostic biomarker for pancreatic cancer. Targeting TROP2 might be a useful treatment approach for patients with pancreatic cancer overexpressing this cell-surface marker.},

note = {Place: England},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{fong_trop2_2008,

title = {TROP2: a novel prognostic marker in squamous cell carcinoma of the oral cavity.},

author = {Dominic Fong and Gilbert Spizzo and Johanna M. Gostner and Guenther Gastl and Patrizia Moser and Clemens Krammel and Stefan Gerhard and Michael Rasse and Klaus Laimer},

doi = {10.1038/modpathol.3801001},

issn = {0893-3952},

year  = {2008},

date = {2008-02-01},

journal = {Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc},

volume = {21},

number = {2},

pages = {186–191},

abstract = {Squamous cell carcinoma is by far the most common type of cancer of the oral cavity, representing more than 90% of all oral cancers. Despite refinement of surgical techniques and adjuvant therapies, the prognosis for patients with oral squamous cell carcinoma remains poor. Identification of prognostic factors related to tumor biology might improve this assessment. Recently, the human trophoblast cell-surface antigen TROP2 was found to be highly expressed in colorectal cancer, correlating with aggressiveness and poor prognosis. Thus, the aim of this study was to investigate TROP2 expression and its prognostic impact in oral squamous cell carcinoma patients. TROP2 expression was examined by immunohistochemistry in a series of 90 patients on a tissue microarray of paraffin-embedded specimens. Survival was calculated using Kaplan-Meier estimates. Parameters found to be of prognostic significance in univariate analysis were verified in a multivariate Cox regression model. TROP2 overexpression was observed in 52 (58%) of the tumor samples. Kaplan-Meier curves showed that TROP2 overexpression was significantly associated with decreased overall survival (P<0.01). Overall survival gradually worsened with increasing TROP2 scores. By univariate analyses, no correlation with conventional clinicopathological features was found. Multivariate Cox regression analysis revealed TROP2 overexpression to be an independent factor predictive of poor disease outcome (P<0.01). These results demonstrate that TROP2 overexpression is an independent prognostic marker in patients with oral squamous cell carcinoma. TROP2 overexpression was detectable in 58% of the tumor samples, indicating it to be a potential novel therapeutic target in squamous cell carcinoma of the oral cavity.},

note = {Place: United States},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{henn_pathogenic_2005,

title = {Pathogenic mutations inactivate parkin by distinct mechanisms.},

author = {Iris H. Henn and Johanna M. Gostner and Peter Lackner and Jörg Tatzelt and Konstanze F. Winklhofer},

doi = {10.1111/j.1471-4159.2004.02854.x},

issn = {0022-3042},

year  = {2005},

date = {2005-01-01},

journal = {Journal of neurochemistry},

volume = {92},

number = {1},

pages = {114–122},

abstract = {Loss of parkin function is the major cause of autosomal recessive Parkinson's disease (ARPD). A wide variety of parkin mutations have been identified in patients; however, the pathophysiological mechanisms leading to the inactivation of mutant parkin are poorly understood. In this study we characterized pathogenic C- and N-terminal parkin mutants and found distinct pathways of parkin inactivation. Deletion of the C terminus abrogated the association of parkin with cellular membranes and induced rapid misfolding and aggregation. Four N-terminal missense mutations, located within the ubiquitin-like domain (UBL), decrease the stability of parkin; as a consequence, these mutants are rapidly degraded by the proteasome. Furthermore, we present evidence that a smaller parkin species of 42 kDa, which is present in extracts prepared from human brain and cultured cells, originates from an internal start site and lacks the N-terminal UBL domain.},

note = {Place: England},

keywords = {},

pubstate = {published},

tppubtype = {article}

}