The Impatient Muse: Germany and the Sturm und Drang

Far from being a forerunner of Weimar Classicism or an addendum to the Enlightenment, the Sturm und Drang is best seen as part of an autonomous culture of impatience—as literature in which Germans, frustrated with their fragmented land, simulated a sense of power and effectiveness that political realities did not afford. This impatience drove not only authors and the characters they created it also drew in German audiences and readers ready to partake vicariously in national sentiments that they otherwise could not have experienced. Alan Leidner sees Lavater's work as a model for dealing with a limiting culture, Goethe's Werther as a subtly arrogant figure, the drama of the "Kraftmensch" as a literature legitimizing the violence of its protagonists, the famous split in the "Urfaust" as the result of Goethe's resistance to the impatience that led many writers to fabricate a German nation that did not exist, and Schiller's "Die Räuber" as a liberating ritual that allowed German audiences to enjoy temporary feelings of national community. He concludes his study with an analysis of J. M. R. Lenz, whose texts recoil unequivocally in the face of the impatient muse

Identification and characterization of microRNAs expressed in the African malaria vector Anopheles funestus life stages using high throughput sequencing

Background: Over the past several years, thousands of microRNAs (miRNAs) have been identified in the genomes of various insects through cloning and sequencing or even by computational prediction. However, the number of miRNAs identified in anopheline species is low and little is known about their role. The mosquito Anopheles funestus is one of the dominant malaria vectors in Africa, which infects and kills millions of people every year. Therefore, small RNA molecules isolated from the four life stages (eggs, larvae, pupae and unfed adult females) of An. funestus were sequenced using next generation sequencing technology. Results: High throughput sequencing of four replicates in combination with computational analysis identified 107 mature miRNA sequences expressed in the An. funestus mosquito. These include 20 novel miRNAs without sequence identity in any organism and eight miRNAs not previously reported in the Anopheles genus but are known in non-anopheles mosquitoes. Finally, the changes in the expression of miRNAs during the mosquito development were determined and the analysis showed that many miRNAs have stage-specific expression, and are co-transcribed and co-regulated during development. Conclusions: This study presents the first direct experimental evidence of miRNAs in An. funestus and the first profiling study of miRNA associated with the maturation in this mosquito. Overall, the results indicate that miRNAs play important roles during the growth and development. Silencing such molecules in a specific life stage could decrease the vector population and therefore interrupt malaria transmission.IS

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

The Impatient Muse

Far from being a forerunner of Weimar Classicism or an addendum to the Enlightenment, the Sturm und Drang is best seen as part of an autonomous culture of impatience—as literature in which Germans, frustrated with their fragmented land, simulated a sense of power and effectiveness that political realities did not afford. This impatience drove not only authors and the characters they created; it also drew in German audiences and readers ready to partake vicariously in national sentiments that they otherwise could not have experienced. Alan Leidner sees Lavater's work as a model for dealing with a limiting culture, Goethe's Werther as a subtly arrogant figure, the drama of the "Kraftmensch" as a literature legitimizing the violence of its protagonists, the famous split in the "Urfaust" as the result of Goethe's resistance to the impatience that led many writers to fabricate a German nation that did not exist, and Schiller's "Die Räuber" as a liberating ritual that allowed German audiences to enjoy temporary feelings of national community. He concludes his study with an analysis of J. M. R. Lenz, whose texts recoil unequivocally in the face of the impatient muse

The Impatient Muse

Far from being a forerunner of Weimar Classicism or an addendum to the Enlightenment, the Sturm und Drang is best seen as part of an autonomous culture of impatience—as literature in which Germans, frustrated with their fragmented land, simulated a sense of power and effectiveness that political realities did not afford. This impatience drove not only authors and the characters they created; it also drew in German audiences and readers ready to partake vicariously in national sentiments that they otherwise could not have experienced. Alan Leidner sees Lavater's work as a model for dealing with a limiting culture, Goethe's Werther as a subtly arrogant figure, the drama of the "Kraftmensch" as a literature legitimizing the violence of its protagonists, the famous split in the "Urfaust" as the result of Goethe's resistance to the impatience that led many writers to fabricate a German nation that did not exist, and Schiller's "Die Räuber" as a liberating ritual that allowed German audiences to enjoy temporary feelings of national community. He concludes his study with an analysis of J. M. R. Lenz, whose texts recoil unequivocally in the face of the impatient muse

Self-rated competences questionnaires from a design perspective

This paper provides a theoretical review of self-rated competences questionnaires. This topic is influenced by the ongoing world-wide reform of higher education, which has led to a focus on the learner outcomes of higher education. Consequently, questionnaires on self-rated competences have increasingly been employed. However, self-ratings are often criticised for their lack of validity. Our intention is to outline some principles of good questionnaire design and to use these principles to contrast questionnaires on self-rated competences. We begin with an overview of research about questionnaire design. Then we introduce seven questionnaires and portray them in terms of their design characteristics. A comparison reveals some significant points: biographical data need to be handled more carefully, and there is an overuse of vague and abstract language. On the positive side, all of the questionnaires that were examined provide reliable sub-scales covering important facets of competences

First report of the safety/tolerability and preliminary antitumor activity of HB-201 and HB-202, an arenavirus-based cancer immunotherapy, in patients with HPV16+ cancers.

Research Funding: Hookipa Biotech Gmbh Background:Human papillomavirus 16 (HPV16) is linked to several cancer types. Treatment options are limited for patients with HPV16 positive (HPV16+) recurrent or metastatic cancers. Generation and maintenance of HPV16+ malignant state require stable expression of HPV16-specific E7 and E6 oncoproteins, also a source of immunogenic neoantigens. HB-201 and HB-202 are replicating live-attenuated vectors based on lymphocytic choriomeningitis virus and Pichinde virus, respectively, which express the same non-oncogenic HPV16 E7E6 fusion protein to induce tumor-specific T-cell responses. This is a first-in-human phase 1/2 study of HB-201 monotherapy and HB-201 & HB-202 alternating 2-vector therapy. Dose escalation is ongoing with a 3+3 design.Methods:Phase 1 is assessing different regimens and dose levels of HB-201 monotherapy and HB-201 & HB-202 alternating 2-vector therapy given intravenously (IV) with or without an initial intratumoral administration. The patient population includes HPV16+ head and neck squamous cell carcinoma (HNSCC) and other HPV16+ cancers. Safety, tolerability, and preliminary antitumor activity by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or immune RECIST are assessed.Results:As of Jan 2021, 25 patients with a median of 3 prior anticancer treatments have been enrolled. All had HPV16+ confirmed genotype; the most common primary site was oropharynx (72%). No dose-limiting toxicities were reported. Treatment-emergent adverse events (TEAEs) occurred in 21 patients (84%), were generally mild or moderate, with events related to study drug reported in 14 patients (56%). TEAEs reported in \u3e10% of patients regardless of causality included fatigue, pyrexia, nausea, decreased appetite, anemia, arthralgia, chills, constipation, diarrhea, hypertension, influenza-like illness, pneumonia, and vomiting. Serious TEAEs developed in 6 patients (24%), including 1 with grade 5 hemorrhagic shock deemed unrelated to study drug. Grade 3 fatigue was the only serious or grade ≥3 TEAE assessed as related to study drug. TEAEs caused no treatment discontinuation. There were 18 patients evaluable for efficacy. For the 16 patients on HB-201 monotherapy, assessment of target lesions showed 2 partial responses (including 1 patient with an unconfirmed immune CR) and 6 patients had stable disease (SD). For the 2 patients on HB-201 & HB-202 alternating therapy, both had SD. So far, the longest duration of response was 4.8 months (144 days) and the maximum decrease in tumor diameter was 60%, both seen in HNSCC patients receiving HB-201 IV.Conclusions:HB-201 monotherapy and HB-201 & HB-202 2-vector alternating therapy were generally well-tolerated and showed preliminary antitumor activity as monotherapy in heavily pre-treated patients with HPV16+ HNSCC and other solid tumors. Clinical trial information: NCT0418021

ICIS 2021 Keynote Address and Awards Ceremony

This is a video recording of the Keynote Address and AIS Awards Ceremony during ICIS 2021 on Monday December 13, 2021 in Austin, Texas. ICIS 2021 is a hybrid conference

A phase I/II study of HB-201, an arenavirus-based cancer immunotherapy, alone, or in combination with anti-PD-1 in patients with HPV16+ cancers.

Background: Human Papillomavirus 16 (HPV16) is linked to several cancer types; treatment options are limited for patients with HPV16+ recurrent or metastatic cancers. The generation and maintenance of the HPV16+ malignant state requires the stable expression of HPV16-specific E7 and E6 oncogenes, which can also serve as immunogenic tumor-associated antigens. HB-201 is a replication-competent live-attenuated vector based on the arenavirus LCMV encoding a non-oncogenic E7 and E6 fusion protein. In preclinical models, both intravenously (IV) and intratumorally (IT) administered HB-201 demonstrate potent immunogenicity by induction of HPV16-specific cytotoxic T cells and associated efficacy. Methods: This is a first in human, Phase I/II study of HB-201 monotherapy or in combination with PD-1 immune checkpoint inhibitor (anti-PD-1) in HPV16+ confirmed recurrent/metastatic cancers. Phase I consists of 2 treatment groups, each conducted with a 3+3 dose escalation design. Group 1 is enrolling patients with HPV16+ head and neck squamous cell carcinoma who will receive HB-201 IV only. Group 2 is enrolling HPV16+ cancer patients with a safely accessible tumor site who will receive HB-201 IT for the first dose, followed by HB-201 IV for subsequent doses (IT-IV). HB-201 will be administered every 21 days. The Phase II component will be conducted with the recommended Phase II doses (RP2Ds) defined in Phase I and will consist of 3 groups: Group A (HB-201 IV only), Group B (HB-201 IV plus anti-PD-1), and Group C (HB-201 IT-IV). Key eligibility criteria include age \u3e 18, ECOG performance status 0-1, confirmed HPV16+ recurrent or metastatic cancer, disease progression from at least 1 systemic standard of care therapy, and measurable disease per RECIST v1.1. The Phase I primary objective is to determine RP2Ds for IV and IT HB-201. The Phase II primary objective is to assess antitumor activity. Secondary endpoints for both phases include safety, tolerability, overall survival, progression-free survival, and duration of response. Exploratory objectives include characterization of immunogenicity of HB-201 and biomarkers associated with immune or antitumor response. Enrollment to Groups 1 and 2 began in December 2019. Clinical trial information: NCT04180215