Neuroökonomie = (Neuroeconomics) : neuronale Mechanismen ökonomischer Entscheidungen

Ökonomische Entscheidungen sind ebenso wie alltägliche Entscheidungen von der Aktivität von Hirnregionen abhängig, die zur Kontrolle verschiedener Teilschritte der Entscheidung beitragen. Aktivierung und Desaktivierung dieser Hirnregionen können mit Hilfe moderner bildgebender Verfahren, wie z.B. der funktionellen Magnet-Resonanz-Tomographie (fMRI) dargestellt werden. Die vorliegende Publikation gibt einen Überblick über das interdisziplinäre wissenschaftliche Arbeitsgebiet der „Neuroökonomie“ – einem jungen Forschungsfeld der Neurowissenschaften. Dieser Überblick ist auf sieben Hauptaspekte ökonomischer und finanzieller Entscheidungen fokusiert: 1. In welcher Weise werden ökonomische Parameter wie Wert und Nutzen einer Belohnung, Gewinn oder Verlust, Risiko und Ungewissheit in spezifischen Hirnregionen abgebildet? 2. In welcher spezifischen Weise tragen anatomisch definierte Areale des Gehirns zum Entscheidungsprozess bei? 3. In welcher Weise sind die Entscheidungsprozesse durch Läsion entscheidungsrelevanter Areale des Gehirns gestört? 4. In welcher Weise sind Hirnregionen, die an den Prozessen der Entscheidung beteiligt sind, miteinander vernetzt, um durch Interaktion die Entscheidung herbeizuführen? 5. In welcher Weise ist der Entscheidungsprozess von Persönlichkeitseigenschaften, von genetischen Variationen neuronaler Funktionen und von physiologischer Regulation, z.B. durch Hormone bestimmt? 6. In welcher Weise hängt der Entscheidungsprozess vom sozialen und kulturellen Umfeld des Entscheiders ab? 7. Auf welche Weise werden bei unvollständiger Information über die Optionen der Entscheidung Heuristiken oder Intuitionen genutzt, und in welcher Weise sind Entscheidungen durch Biases beeinflussbar? Der zentrale Teil dieser Publikation gibt einen zusammenfassenden Überblick (review) über die Ergebnisse neuroökonomischer Studien, die die fMRI-Technik nutzen (bis Juni 2010)

CoCoss-Trial: Concurrent Comparison of Self-Sampling Devices for HPV-Detection

High-risk human papillomavirus (hr-HPV) infection of the cervicovaginal tract is known to be the major cause of cervical cancer. Similar to various other countries, Germany introduced an organized combined screening including cytology and HPV testing in 2020. The participation rate was around 70% in the past. Self-testing for hr-HPV infections could be an option to increase the participation rate. Two dry vaginal self-sampling devices and a device for the self-collection of first-void urine were evaluated in combination with a PCR-based hr-HPV test regarding their clinical performance (sensitivity for high-grade cervical intraepithelial neoplasia, CIN 2+). A cervical smear taken by a clinician during colposcopy was used as reference. This open prospective multicenter trial recruited patients referred to the two participating colposcopy clinics (Hannover Medical School and IZD Hannover, Germany) with abnormal results from cervical cancer screening from 05/2020 to 11/2020. All patients received three CE-certified self-sampling devices (FLOQSwabs, COPAN, Italy; Evalyn Brush, Rovers Medical Devices, the Netherlands; Colli-Pee FV-5000, Novosanis, Wijnegem, Belgium) with instructions to read and apply at home in a pre-specified alternating order without medical assistance. HPV testing was performed after adequate preservation and DNA extraction. Histological results from colposcopy or cervical excisional surgery after self-sampling were used as the gold-standard. The data of 65 patients were analyzed. All invasive cancer cases and over 90% of the CIN 3 lesions were found to be hr-HPV positive with all three self-collection devices. All devices were considered easy to use without any difficulties following the written instructions. Hr-HPV testing of self-collected first-void urine and dry vaginal self-samples showed a high sensitivity for CIN 3+ comparable to that of a clinician-taken smear. Self-sampling was well accepted as it is convenient and easy to use

Post-translational control of IL-1β via the human papillomavirus type 16 E6 oncoprotein: a novel mechanism of innate immune escape mediated by the E3-ubiquitin ligase E6-AP and p53.

Infections with high-risk human papillomaviruses (HPVs) are causally involved in the development of anogenital cancer. HPVs apparently evade the innate immune response of their host cells by dysregulating immunomodulatory factors such as cytokines and chemokines, thereby creating a microenvironment that favors malignancy. One central key player in the immune surveillance interactome is interleukin-1 beta (IL-1β) which not only mediates inflammation, but also links innate and adaptive immunity. Because of its pleiotropic physiological effects, IL-1β production is tightly controlled on transcriptional, post-translational and secretory levels. Here, we describe a novel mechanism how the high-risk HPV16 E6 oncoprotein abrogates IL-1β processing and secretion in a NALP3 inflammasome-independent manner. We analyzed IL-1β regulation in immortalized keratinocytes that harbor the HPV16 E6 and/or E7 oncogenes as well as HPV-positive cervical tumor cells. While in primary and in E7-immortalized human keratinocytes the secretion of IL-1β was highly inducible upon inflammasome activation, E6-positive cells did not respond. Western blot analyses revealed a strong reduction of basal intracellular levels of pro-IL-1β that was independent of dysregulation of the NALP3 inflammasome, autophagy or lysosomal activity. Instead, we demonstrate that pro-IL-1β is degraded in a proteasome-dependent manner in E6-positive cells which is mediated via the ubiquitin ligase E6-AP and p53. Conversely, in E6- and E6/E7-immortalized cells pro-IL-1β levels were restored by siRNA knock-down of E6-AP and simultaneous recovery of functional p53. In the context of HPV-induced carcinogenesis, these data suggest a novel post-translational mechanism of pro-IL-1β regulation which ultimately inhibits the secretion of IL-1β in virus-infected keratinocytes. The clinical relevance of our results was further confirmed in HPV-positive tissue samples, where a gradual decrease of IL-1β towards cervical cancer could be discerned. Hence, attenuation of IL-1β by the HPV16 E6 oncoprotein in immortalized cells is apparently a crucial step in viral immune evasion and initiation of malignancy

Association of two genomic variants with HPV type-specific risk of cervical cancer

Problem: Human papillomavirus infection is integral to developing invasive cervical cancer in the majority of patients. In a recent genome-wide association study, rs9357152 and rs4243652 have been associated with seropositivity for HPV16 or HPV18, respectively. It is unknown whether these variants also associate with cervical cancer triggered by either HPV16 or HPV18. Methods: We investigate whether the two HPV susceptibility variants show association with type-specific cervical cancer in a genetic case-control study with cases stratified by HPV16 or HPV18, respectively. We further tested whether rs9357152 modulates gene expression of any of 36 genes at the human leukocyte antigen locus in 256 cervical tissues. Results: rs9357152 was associated with invasive HPV16-positive cervical cancer (OR 1.33, 95%CI 1.03–1.70, p = 0.03), and rs4243652 was associated with HPV18-positive adenocarcinomas (OR 2.96, 95%CI 1.18–7.41, p = 0.02). These associations remained borderline significant after testing against different sets of controls. rs9357152 was found to be an eQTL for HLA-DRB1 in HPV-positive cervical tissues (pANOVA = 0.0009), with the risk allele lowering mRNA levels. Conclusions: We find evidence that HPV seropositivity variants at chromosome 6 and 14 may modulate type-specific cervical cancer risk. rs9357152 may exert its effect through regulating HLA-DRB1 induction in the presence of HPV. In regard of multiple testing, these results need to be confirmed in larger studies

Expression and secretion of IL-1β in human primary keratinocytes and HPV-positive cell lines.

<p>A) Quantification of secreted IL-1β (expressed as pg/ml) by ELISA in human primary keratinocytes (PK), keratinocytes immortalized by individual oncogenes (E6, E7, E6/E7) and HPV16/18-positive cervical carcinoma cell lines (SiHa, CaSki, HeLa, respectively) 24 h after infection with a recombinant GFP-expressing adenovirus 5 (Ad) in comparison to uninfected cells. B) Quantification of basal intracellular IL-1β levels by ELISA. C) Western blot analysis of pro-IL-1β in human primary keratinocytes (PK) and HPV-positive cells. Actin was used as a loading control. D) qPCR analysis of IL-1β cDNA obtained from PK and HPV-positive cells (Ordinate: expressed as fold changes using the average IL-1β steady state level of 3 different primary human keratinocyte preparations PK cells as a reference which was arbitrarily set as 1. The graphs in A, B and D represent the mean values (± SEM) of three independent experiments. ANOVA ***p<0.05.</p

Analysis of IL-1β expression in normal and HPV16-positive cervical tissues.

<p>A) Immunohistochemical analysis of IL-1β expression in normal epithelium and HPV-positive lesions differing in their progression grades CIN I to CIN III and cervical tumors; scale bars represent 25 µm. B) qPCR analysis of IL-1β cDNA derived from samples negative for intraepithelial lesion and malignancy (NT), different HPV-positive lesions (CIN I, II, III) and cervical tumors (CxCa); ordinate: expression as fold changes using SiHa cells as reference which was arbitrarily set as 1. The pictures in A are a representative example of 25 biopsies analyzed from normal tissue (n = 5) and HPV-positive lesions of different donors (n = 25). The box-and-whisker blot in B represents the mean values from three to five samples for each group depicted in the graph (± SEM). ANOVA *p<0.01.</p

Proteasome inhibition or knock-down of E6-AP increases the levels of pro-IL-1β in immortalized E6-positive cells.

<p>A) ELISA of intracellular IL-1β from untreated immortalized HPV-positive cells and cells incubated with 10 µM of the proteasome inhibitor MG132 for 6 h. B) Western blot analysis of pro-IL1β and p53 in immortalized keratinocytes after inhibition of deubiquitinases using PR-619 (10 µM) for 6 h prior to protein extraction. C) Detection of poly-ubiquitinated pro-IL-1β in immortalized keratinocytes by Western blotting. Cells were treated with MG132 for 6 h prior to protein extraction and pull-down of ubiquitinated proteins was performed by the tandem ubiquitin-binding entities technique (TUBE-PD, right panel). Left panel: input, representing 2.5% of the total protein extract. D) Confocal microscopy analysis of IL-1β (green) in immE6 cells after knock-down of E6-AP by siRNA or scrambled siRNA delivery used as a control. Nuclei (blue) were stained using Hoechst dye solution; scale bars represent 10 µm. E) Western blot analysis of pro-IL-1β after the knock-down of E6-AP. F) ELISA of intracellular IL-1β from immortalized HPV-positive cells after the knock-down of E6-AP by siRNA (+) or control knock-down.(−) G) ELISA of IL-1β secretion from immortalized HPV-positive cells after E6-AP knock-down and/or after NALP3 inflammasome activation using 50 µM of nigericine for 6 h. H) Knock-down of p53 and/or E6-AP in immortalized cells. Cells were transfected with 30 pmoles of the respective siRNA against E6-AP or p53 and incubated for 72 h prior to protein extraction and Western blot analysis. The bar graphs shown in A (ANOVA ***p<0.05), D (ANOVA ***p<0.001, **p<0.01) F and G (ANOVA ***p<0.001) represent the mean levels (± SEM) of three independent experiments.</p

Caspase-1 activity did not account for decreased IL-1β in E6-positive cells.

<p>A) RT-PCR analysis of caspase-1 mRNA in comparison to the GAPDH steady state levels in PK and HPV-positive immortalized keratinocytes. B) Fluorometric measurement of caspase-1 activity was performed incubating the cells for 4 h at 37°C with 20 µM of the specific caspase-1 substrate R110-YVAD. RFU: Relative fluorescence units. C) Quantification of intracellular IL-1β levels by ELISA after 5 h of caspase-1 inhibition using 250 nM of caspase-1 inhibitor. The graphs in B and C represent the mean values (± SEM) of three independent experiments. ANOVA **p<0.01, ***p<0.001.</p