A novel, integrated in vitro carcinogenicity test to identify genotoxic and non-genotoxic carcinogens using human lymphoblastoid cells

Human exposure to carcinogens occurs via a plethora of environmental sources, with 70–90% of cancers caused by extrinsic factors. Aberrant phenotypes induced by such carcinogenic agents may provide universal biomarkers for cancer causation. Both current in vitro genotoxicity tests and the animal-testing paradigm in human cancer risk assessment fail to accurately represent and predict whether a chemical causes human carcinogenesis. The study aimed to establish whether the integrated analysis of multiple cellular endpoints related to the Hallmarks of Cancer could advance in vitro carcinogenicity assessment. Human lymphoblastoid cells (TK6, MCL-5) were treated for either 4 or 23 h with 8 known in vivo carcinogens, with doses up to 50% Relative Population Doubling (maximum 66.6 mM). The adverse effects of carcinogens on wide-ranging aspects of cellular health were quantified using several approaches; these included chromosome damage, cell signalling, cell morphology, cell-cycle dynamics and bioenergetic perturbations. Cell morphology and gene expression alterations proved particularly sensitive for environmental carcinogen identification. Composite scores for the carcinogens’ adverse effects revealed that this approach could identify both DNA-reactive and non-DNA reactive carcinogens in vitro. The richer datasets generated proved that the holistic evaluation of integrated phenotypic alterations is valuable for effective in vitro risk assessment, while also supporting animal test replacement. Crucially, the study offers valuable insights into the mechanisms of human carcinogenesis resulting from exposure to chemicals that humans are likely to encounter in their environment. Such an understanding of cancer induction via environmental agents is essential for cancer prevention

Distinct predictive biomarker candidates for response to anti-CTLA-4 and anti-PD-1 immunotherapy in melanoma patients

Background: While immune checkpoint blockade has greatly improved clinical outcomes in diseases such as melanoma, there remains a need for predictive biomarkers to determine who will likely benefit most from which therapy. To date, most biomarkers of response have been identified in the tumors themselves. Biomarkers that could be assessed from peripheral blood would be even more desirable, because of ease of access and reproducibility of sampling. Methods: We used mass cytometry (CyTOF) to comprehensively profile peripheral blood of melanoma patients, in order to find predictive biomarkers of response to anti-CTLA-4 or anti-PD-1 therapy. Using a panel of ~ 40 surface and intracellular markers, we performed in-depth phenotypic and functional immune profiling to identify potential predictive biomarker candidates. Results: Immune profiling of baseline peripheral blood samples using CyTOF revealed that anti-CTLA-4 and anti-PD-1 therapies have distinct sets of candidate biomarkers. The distribution of CD4+ and CD8+ memory/non-memory cells and other memory subsets was different between responders and non-responders to anti-CTLA-4 therapy. In anti-PD-1 (but not anti-CTLA-4) treated patients, we discovered differences in CD69 and MIP-1β expressing NK cells between responders and non-responders. Finally, multivariate analysis was used to develop a model for the prediction of response. Conclusions: Our results indicate that anti-CTLA-4 and anti-PD-1 have distinct predictive biomarker candidates. CD4+ and CD8+ memory T cell subsets play an important role in response to anti-CTLA-4, and are potential biomarker candidates. For anti-PD-1 therapy, NK cell subsets (but not memory T cell subsets) correlated with clinical response to therapy. These functionally active NK cell subsets likely play a critical role in the anti-tumor response triggered by anti-PD-1. Electronic supplementary material The online version of this article (10.1186/s40425-018-0328-8) contains supplementary material, which is available to authorized users

Improving Specificity for Ovarian Cancer Screening Using a Novel Extracellular Vesicle–Based Blood Test: Performance in a Training and Verification Cohort

The low incidence of ovarian cancer (OC) dictates that any screening strategy needs to be both highly sensitive and highly specific. This study explored the utility of detecting multiple colocalized proteins or glycosylation epitopes on single tumor-associated extracellular vesicles from blood. The novel Mercy Halo Ovarian Cancer Test (OC Test) uses immunoaffinity capture of tumor-associated extracellular vesicles, followed by proximity-ligation real-time quantitative PCR to detect combinations of up to three biomarkers to maximize specificity and measures multiple combinations to maximize sensitivity. A high-grade serous carcinoma (HGSC) case-control training set of EDTA plasma samples from 397 women was used to lock down the test design, the data interpretation algorithm, and the cutoff between cancer and noncancer. Performance was verified and compared with cancer antigen 125 in an independent blinded case-control set of serum samples from 390 women (132 controls, 66 HGSC, 83 non-HGSC OC, and 109 benign). In the verification study, the OC Test showed a specificity of 97.0% (128/132; 95% CI, 92.4%–99.6%), a HGSC sensitivity of 97.0% (64/66; 95% CI, 87.8%–99.2%), and an area under the curve of 0.97 (95% CI, 0.93–0.99) and detected 73.5% (61/83; 95% CI, 62.7%–82.6%) of the non-HGSC OC cases. This test exhibited fewer false positives in subjects with benign ovarian tumors, nonovarian cancers, and inflammatory conditions when compared with cancer antigen 125. The combined sensitivity and specificity of this new test suggests it may have potential in OC screening

Antepipona assmanni nov.sp. und Antepipona aubrechti nov.sp., zwei neue Arten aus Kenia (Hymenoptera: Vespidae: Eumeninae)

Gusenleitner, J., Gusenleitner, F. (2010): Antepipona assmanni nov.sp. und Antepipona aubrechti nov.sp., zwei neue Arten aus Kenia (Hymenoptera: Vespidae: Eumeninae). Linzer biologische Beiträge 42 (1): 711-72

Eine neue Gattung und zwei neue Faltenwespen aus der Orientalischen Region (Hymenoptera, Vespidae, Eumeninae)

Gusenleitner, J., Gusenleitner, F. (2013): Eine neue Gattung und zwei neue Faltenwespen aus der Orientalischen Region (Hymenoptera, Vespidae, Eumeninae). Linzer biologische Beiträge 45 (1): 133-139, DOI: 10.5281/zenodo.534099

Dokumente zum wissenschaftlichen Opus von Horst Aspöck für die Periode 2004 bis 2014 anlässlich seines 75. Geburtstags

Gusenleitner, F. (2014): Dokumente zum wissenschaftlichen Opus von Horst Aspöck für die Periode 2004 bis 2014 anlässlich seines 75. Geburtstags. Linzer biologische Beiträge 46 (2): 1843-188

Chronologisch geordnetes Verzeichnis der Publikationen 586b (2004) bis 650 (2009) von Horst Aspöck

Gusenleitner, F. (2009): Chronologisch geordnetes Verzeichnis der Publikationen 586b (2004) bis 650 (2009) von Horst Aspöck. Linzer biologische Beiträge 41 (1): 973-99

Dr. Josef Gusenleitner zum 80er - ein Leben den Vespiden gewidmet

Gusenleitner, F. (2009): Dr. Josef Gusenleitner zum 80er - ein Leben den Vespiden gewidmet. Linzer biologische Beiträge 41 (2): 1001-105

Abb. 19-23 in Beitrag zur Kenntnis der Stelis-Arten Spaniens (Hymenoptera, Apidae, Megachilinae)

Abb. 19-23: (19-21) Stelis hispanica HT: (19) Metatarsus III, (20) Gestaltung der Sternite, (21) Behaarung des Mesonotums; (22-23) Stelis annulata: (22) Gestaltung der Sternite, (23) Behaarung des Mesonotums.Published as part of <i>Schwarz, M. & Gusenleitner, F., 2010, Beitrag zur Kenntnis der Stelis-Arten Spaniens (Hymenoptera, Apidae, Megachilinae), pp. 1311-1321 in Linzer biologische Beiträge 42 (2)</i> on page 1318, DOI: <a href="http://zenodo.org/record/10106167">10.5281/zenodo.10106167</a&gt