Franziska Hartung

Potassium channels as tumour markers

An increasing number of ion channels are being found to be causally involved in diseases, giving rise to the new field of “channelopathies”. Cancer is no exception, and several ion channels have been linked to tumour progression. Among them is the potassium channel EAG (Ether‐a‐go‐go). Over 75% of tumours have been tested positive using a monoclonal antibody specific for EAG, while inhibition of this channel decreased the proliferation of EAG expressing cells. The inhibition of EAG is accomplished using RNA interference, functional anti‐EAG1 antibodies, or (unspecific) EAG channel blockers. Fluorescently labelled recombinant Fab fragments recognizing EAG allow the distribution of EAG to be visualized in an in vivo mouse tumour model.

Tumor cell-selective apoptosis induction through targeting of KV10.1 via bifunctional TRAIL antibody

BackgroundThe search for strategies to target ion channels for therapeutic applications has become of increasing interest. Especially, the potassium channel KV10.1 (Ether-á-go-go) is attractive as target since this surface protein is virtually not detected in normal tissue outside the central nervous system, but is expressed in approximately 70% of tumors from different origins.MethodsWe designed a single-chain antibody against an extracellular region of KV10.1 (scFv62) and fused it to the human soluble TRAIL. The KV10.1-specific scFv62 antibody -TRAIL fusion protein was expressed in CHO-K1 cells, purified by chromatography and tested for biological activity.ResultsProstate cancer cells, either positive or negative for KV10.1 were treated with the purified construct. After sensitization with cytotoxic drugs, scFv62-TRAIL induced apoptosis only in KV10.1-positive cancer cells, but not in non-tumor cells, nor in tumor cells lacking KV10.1 expression. In co-cultures with KV10.1-positive cancer cells the fusion protein also induced apoptosis in bystander KV10.1-negative cancer cells, while normal prostate epithelial cells were not affected when present as bystander.ConclusionsKV10.1 represents a novel therapeutic target for cancer. We could design a strategy that selectively kills tumor cells based on a KV10.1-specific antibody.

Taking perspective: Personal pronouns affect experiential aspects of literary reading

Personal pronouns have been shown to influence cognitive perspective taking during comprehension. Studies using single sentences found that 3rd person pronouns facilitate the construction of a mental model from an observer’s perspective, whereas 2nd person pronouns support an actor’s perspective. The direction of the effect for 1st person pronouns seems to depend on the situational context. In the present study, we investigated how personal pronouns influence discourse comprehension when people read fiction stories and if this has consequences for affective components like emotion during reading or appreciation of the story. We wanted to find out if personal pronouns affect immersion and arousal, as well as appreciation of fiction. In a natural reading paradigm, we measured electrodermal activity and story immersion, while participants read literary stories with 1st and 3rd person pronouns referring to the protagonist. In addition, participants rated and ranked the stories for appreciation. Our results show that stories with 1st person pronouns lead to higher immersion. Two factors—transportation into the story world and mental imagery during reading—in particular showed higher scores for 1st person as compared to 3rd person pronoun stories. In contrast, arousal as measured by electrodermal activity seemed tentatively higher for 3rd person pronoun stories. The two measures of appreciation were not affected by the pronoun manipulation. Our findings underscore the importance of perspective for language processing, and additionally show which aspects of the narrative experience are influenced by a change in perspective.

Readers select a comprehension mode independent of pronoun: Evidence from fMRI during narrative comprehension

HighlightsSimulation of perspective was tested with personal pronouns in short stories.FMRI revealed no difference between action events with 1st or 3rd person pronouns.Behavioral data revealed 3 different perspective taking types.Perspective taking types activate different neural networks during comprehension.Readers seem to select from different modes in situation model construction. ABSTRACT Perspective is a crucial feature for communicating about events. Yet it is unclear how linguistically encoded perspective relates to cognitive perspective taking. Here, we tested the effect of perspective taking with short literary stories. Participants listened to stories with 1st or 3rd person pronouns referring to the protagonist, while undergoing fMRI. When comparing action events with 1st and 3rd person pronouns, we found no evidence for a neural dissociation depending on the pronoun. A split sample approach based on the self‐reported experience of perspective taking revealed 3 comprehension preferences. One group showed a strong 1st person preference, another a strong 3rd person preference, while a third group engaged in 1st and 3rd person perspective taking simultaneously. Comparing brain activations of the groups revealed different neural networks. Our results suggest that comprehension is perspective dependent, but not on the perspective suggested by the text, but on the reader’s (situational) preference.

Guiding TRAIL to cancer cells through Kv10.1 potassium channel overcomes resistance to doxorubicin

Resisting cell death is one of the hallmarks of cancer, and represents a common problem resulting in ineffective cancer therapy. To overcome resistance to apoptosis, we designed an antibody-based therapy strategy using Kv10.1 as a target. Kv10.1 is a voltage-gated potassium channel, which has been identified as a tumor marker several years ago. The agent consists of a Kv10.1-specific single-chain antibody fused to the soluble tumor necrosis factor-related apoptosis-inducing ligand (scFv62-TRAIL). We combined scFv62-TRAIL with different chemotherapeutic drugs, all of which failed to induce apoptosis when used alone. In the combination, we could overcome the resistance and selectively induce apoptosis. Among the drugs, doxorubicin showed the most promising effect. Additionally, we observed improved efficacy by pre-treating the cells with doxorubicin before scFv62-TRAIL application. Expression analysis of the TRAIL death receptors suggests a doxorubicin-induced increase in the abundance of receptors as the mechanism for sensitization. Furthermore, we confirmed the anti-tumor effect and efficacy of our combination strategy in vivo in SCID mice bearing subcutaneous tumors. In conclusion, we propose a novel strategy to overcome resistance to chemotherapy in cancer cells. Doxorubicin and scFv62-TRAIL reciprocally sensitize the cells to each other, specifically in Kv10.1-positive tumor cells.

When Fiction Is Just as Real as Fact: No Differences in Reading Behavior between Stories Believed to be Based on True or Fictional Events

Experiments have shown that compared to fictional texts, readers read factual texts faster and have better memory for described situations. Reading fictional texts on the other hand seems to improve memory for exact wordings and expressions. Most of these studies used a “newspaper” vs. “literature” comparison. In the present study, we investigated the effect of readers expectation to whether information is true or fictional with a subtler manipulation by labeling short stories as either based on true or fictional events. In addition, we tested whether narrative perspective or individual preference in perspective taking affects reading true or fictional stories differently. In an online experiment, participants (final N = 1,742) read one story which was introduced as based on true events or as fictional (factor fictionality). The story could be narrated in either 1st or 3rd person perspective (factor perspective). We measured immersion in and appreciation of the story, perspective taking, as well as memory for events. We found no evidence that knowing a story is fictional or based on true events influences reading behavior or experiential aspects of reading. We suggest that it is not whether a story is true or fictional, but rather expectations toward certain reading situations (e.g., reading newspaper or literature) which affect behavior by activating appropriate reading goals. Results further confirm that narrative perspective partially influences perspective taking and experiential aspects of reading.