First-in-Human Clinical Trial of Oral ONC201 in Patients with Refractory Solid Tumors

Purpose: ONC201 is a small-molecule selective antagonist of the G protein–coupled receptor DRD2 that is the founding member of the imipridone class of compounds. A first-in-human phase I study of ONC201 was conducted to determine its recommended phase II dose (RP2D). Experimental Design: This open-label study treated 10 patients during dose escalation with histologically confirmed advanced solid tumors. Patients received ONC201 orally once every 3 weeks, defined as one cycle, at doses from 125 to 625 mg using an accelerated titration design. An additional 18 patients were treated at the RP2D in an expansion phase to collect additional safety, pharmacokinetic, and pharmacodynamic information. Results: No grade \u3e 1 drug-related adverse events occurred, and the RP2D was defined as 625 mg. Pharmacokinetic analysis revealed a Cmax of 1.5 to 7.5 μg/mL (∼3.9–19.4 μmol/L), mean half-life of 11.3 hours, and mean AUC of 37.7 h·μg/L. Pharmacodynamic assays demonstrated induction of caspase-cleaved keratin 18 and prolactin as serum biomarkers of apoptosis and DRD2 antagonism, respectively. No objective responses by RECIST were achieved; however, radiographic regression of several individual metastatic lesions was observed along with prolonged stable disease (\u3e 9 cycles) in prostate and endometrial cancer patients. Conclusions: ONC201 is a selective DRD2 antagonist that is well tolerated, achieves micromolar plasma concentrations, and is biologically active in advanced cancer patients when orally administered at 625 mg every 3 weeks

Youthful Internationalism in the Age of ‘Socialism in One Country’: Komsomol'tsy, Pioneers and ‘World Revolution’ in the Interwar Period

This article examines the complex and multifaceted engagement of young Soviet communists with the idea of revolutionary internationalism and international solidarity in the interwar period. In spite of the introduction of the official doctrine of ‘Socialism in One Country’ and the ritualization of internationalism in in the 1920s, youth activists continued to encounter the powerful charismatic idea of ‘world revolution’. Moscow’s central role in the Communist International and developments in Asia and Europe meant that the members of the Pioneer organization and the Komsomol had to engage with revolutionary events abroad through the official discourse as well as through their league’s practices. The article seeks to reveal the interplay and tensions between the Komsomol’s official rhetoric and policies concerning its leading role in the international communist youth movement and the idiosyncratic revolutionary identities and beliefs of young activists. By examining the shifting rhetoric and realities in expressions and enactments of international solidarity by young communists, the paper will question the potency of the idea of ‘revolutionary internationalism’ amongst the communist youth movement and its significance in the intergenerational discourse

Web-based mindfulness and skills-based distress reduction for patients with cancer: study protocol of the multicentre, randomised, controlled confirmatory intervention trial Reduct

IntroductionMany patients with cancer experience severe psychological distress, but as a result of various barriers, few of them receive psycho-oncological support. E-mental health interventions try to overcome some of these barriers and the limitation of healthcare offers, enabling patients with cancer to better cope with psychological distress. In the proposed trial, we aim to assess the efficacy and cost-effectiveness of the manualised e-mental health intervention Make It Training- Mindfulness-Based and Skills-Based Distress Reduction in Oncology. Make It Training is a self-guided and web-based psycho-oncological intervention, which includes elements of cognitive behavioural therapy, mindfulness-based stress reduction and acceptance and commitment therapy. The training supports the patients over a period of 4 months. We expect the Make It Training to be superior to treatment as usual optimised (TAU-O) in terms of reducing distress after completing the intervention (T1, primary endpoint).Methods and analysisThe study comprises a multicentre, prospective, randomised controlled confirmatory interventional trial with two parallel arms. The proposed trial incorporates four distinct measurement time points: the baseline assessment before randomisation, a post-treatment assessment and 3 and 6 month follow-up assessments. We will include patients who have received a cancer diagnosis in the past 12 months, are in a curative treatment setting, are 18–65 years old, have given informed consent and experience high perceived psychological distress (Hospital Anxiety and Depression Scale ≥13) for at least 1 week. Patients will be randomised into two groups (Make It vs TAU-O). The aim is to allocate 600 patients with cancer and include 556 into the intention to treat analysis. The primary endpoint, distress, will be analysed using a baseline-adjusted ANCOVA for distress measurement once the intervention (T1) has been completed, with study arm as a binary factor, baseline as continuous measurement and study centre as an additional categorical covariate.Ethics and disseminationThe Ethics Committee of the Medical Faculty Essen has approved the study (21-10076-BO). Results will be published in peer-reviewed journals, conference presentations, the project website, and among self-help organisations.Trial registration numberGerman Clinical Trial Register (DRKS); DRKS-ID: DRKS00025213

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

Deutsche Missions- und Kolonialpädagogik in Dokumenten. Eine kommentierte Quellensammlung aus den Afrikabeständen deutschsprachiger Archive 1884 - 1914

Die vorliegende kommentierte Dokumentensammlung zur deutschen Missions- und Kolonialpädagogik … versammelt – thematisch gruppiert – pädagogische Dokumente aus bzw. zu den deutschen Afrika-Kolonien. Das Buch enthält Übersichtskapitel zur Struktur und Praxis des Bildungswesens in den jeweiligen Kolonialgebieten und inhaltlich ausgerichtete Beiträge zur Sprachenfrage, Mädchenbildung, beruflich-praktischen Ausbildung, zum Lehrpersonal und zu den Ausbildungswegen von Afrikanern im damaligen Deutschland. Die Quellen stammen aus evangelischen, katholischen und regierungsamtlichen Archiven und sind transkribiert und kommentiert, um den Leserinnen und Lesern den Zugang zur Bildungsrealität in den deutschen Kolonien zu erleichtern. (DIPF/Orig.

Close-up fluorescence image time series of the abdomen and the head.

<p>The subject received two consecutive intravenous bolus injections of 25’s field of view was on the abdomen. For the second bolus one hour later, the field of view was on the subject’s head. ICG bolus administration starts at time 0 seconds. Images are divided by a background image to correct for inhomogeneous distribution of the exciting laser light and baseline subtracted. Color coding of fluorescence intensity (a.u.) is equally scaled as indicated by the color bar except for the first two columns, wherecolor bar limits are [0 100].</p