De Jonge Research Articles

Theoretical properties of the MiCRO negotiation strategy

Recently, we have introduced a new algorithm for automated negotiation, called MiCRO, which, despite its simplicity, outperforms many state-of-the-art negotiation strategies (de Jonge, in: Raedt (ed) Proceedings of the thirty-first international joint conference on artificial intelligence, ijcai.org, Vienna, Austria, 2022). Furthermore, we claimed that under certain conditions which typically hold in the Automated Negotiating Agents Competition (ANAC), it is a game-theoretically optimal strategy. The goal of this paper is to formally prove those claims. Specifically, we define ‘negotiation’ as an extensive-form game and define the class of consistent strategies for this game, which consists of those strategies that satisfy a number of rationality criteria. We then prove that under the above mentioned conditions MiCRO is a best response against itself among all consistent negotiation strategies. Furthermore, we define the notion of a balanced negotiation domain, which is a domain in which two MiCRO agents would always come to an optimal agreement. Finally, we show that many of the domains used in ANAC indeed happen to be (approximately) balanced. The importance of this work is that if we know under which conditions MiCRO is theoretically optimal, then we can use this to test to what extent other negotiation algorithms are able to achieve similar results to MiCRO when applied under those same conditions. Furthermore, it would help researchers to design more challenging test cases for automated negotiation in which MiCRO is not optimal.

On matching and periodicity for (N,α)\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$(N,\\alpha )$$\\end{document}-expansions

Recently a new class of continued fraction algorithms, the (N,α\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$(N,\\alpha $$\\end{document})-expansions, was introduced in Kraaikamp and Langeveld (J Math Anal Appl 454(1):106–126, 2017) for each N∈N\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$N\\in \\mathbb {N}$$\\end{document}, N≥2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$N\\ge 2$$\\end{document} and α∈(0,N-1]\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\alpha \\in (0,\\sqrt{N}-1]$$\\end{document}. Each of these continued fraction algorithms has only finitely many possible digits. These (N,α)\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$(N,\\alpha )$$\\end{document}-expansions ‘behave’ very different from many other (classical) continued fraction algorithms; see also Chen and Kraaikamp (Matching of orbits of certain n-expansions with a finite set of digits (2022). To appear in Tohoku Math. J arXiv:2209.08882), de Jonge and Kraaikamp (Integers 23:17, 2023), de Jonge et al. (Monatsh Math 198(1):79–119, 2022), Nakada (Tokyo J Math 4(2):399–426, 1981) for examples and results. In this paper we will show that when all digits in the digit set are co-prime with N, which occurs in specified intervals of the parameter space, something extraordinary happens. Rational numbers and certain quadratic irrationals will not have a periodic expansion. Furthermore, there are no matching intervals in these regions. This contrasts sharply with the regular continued fraction and more classical parameterised continued fraction algorithms, for which often matching is shown to hold for almost every parameter. On the other hand, for α\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\alpha $$\\end{document} small enough, all rationals have an eventually periodic expansion with period 1. This happens for all α\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\alpha $$\\end{document} when N=2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$N=2$$\\end{document}. We also find infinitely many matching intervals for N=2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$N=2$$\\end{document}, as well as rationals that are not contained in any matching interval.

Abstract CT095: Phase 1 evaluation of triple therapy with boserolimab (anti-CD27 agonist), pembrolizumab, and chemotherapy in patients with triple-negative breast cancer (TNBC) with PD-L1 combined positive score (CPS) <10: Safety, antitumor activity, and association between biomarkers and response

Abstract Background: Pembrolizumab (pembro) plus chemotherapy (chemo) is an approved therapy for patients (pts) with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS ≥10) based on results from KEYNOTE-355. However, there is unmet need for effective treatment options in pts with PD-L1 CPS <10. In a first-in-human, open-label, phase 1 study (NCT03396445), treatment with escalating doses of the humanized anti-CD27 agonist boserolimab (MK-5890) alone and with pembro had acceptable safety and preliminary evidence of antitumor activity in pts with advanced solid tumors. We report results for a dose-expansion cohort of this study in pts with metastatic TNBC and PD-L1 CPS <10 tumors who received first-line triple therapy with boserolimab, pembro, and chemo. Exploratory analyses in this cohort assessed the association of baseline T-cell-inflamed gene expression profile (TcellinfGEP) and tumor mutational burden (TMB) with ORR. Methods: This dose-expansion cohort enrolled pts aged ≥18 y with previously untreated locally recurrent inoperable or metastatic TNBC, measurable disease per RECIST v1.1, ECOG PS of 0/1, and tumors expressing PD-L1 at the cutoff of CPS <10 per PD-L1 IHC 22C3 pharmDx (local or central testing). Pts received boserolimab 30 mg IV Q6W plus pembro 400 mg IV Q6W for 18 cycles plus nab-paclitaxel 100 mg/m2 (3 weeks on [days 1, 8, and 15]/1 week off). Primary objectives were safety/tolerability. A secondary objective was ORR per RECIST v1.1 by investigator assessment. Baseline TcellinfGEP was assessed using the NanoString PCI assay (N=31); TMB was assessed using the Illumina TSO500 mutational panel assay (N=21). Results: 41 pts were enrolled in the dose-expansion cohort. Median study follow-up at data cutoff (Apr 25, 2023) was 11.1 (range, 2.2-20.5) mo. The most common treatment-related AEs were fatigue (51.2%), pruritus (51.2%), and alopecia (46.3%). Grade 3/4 treatment-related AEs occurred in 56.1% of pts (23/41); no grade 5 treatment-related AEs occurred. 9.8% of pts (4/41) discontinued ≥1 study treatment due to treatment-related AEs. Confirmed ORR was 46.3% (95% CI, 30.7%-62.6%), with 2 CRs and 17 PRs; 14 pts had SD, 5 had PD, and 3 had no postbaseline assessment at data cutoff. Median PFS was 10.3 (95% CI, 4.2-not reached) mo. No clear association between TcellinfGEP or TMB and confirmed ORR was observed; responses were observed in pts with non-TcellinfGEP-high (less than −0.318) and non-TMB-high (<10 mut/Mb) tumors. Conclusions: In pts with TNBC and tumors expressing PD-L1 at the cutoff of CPS <10, triple therapy with boserolimab, pembro, and chemo had acceptable safety and showed preliminary evidence of antitumor activity regardless of baseline TcellinfGEP expression or TMB status. Citation Format: Carlos Rojas, Bernard Gaston Doger de Spéville, Seock-Ah Im, Ronnie Shapira-Frommer, María De Miguel, Lucía González Cortijo, Margarita Romeo Marin, Maja de Jonge, Mark Ayers, Yiwei Zhang, Song Zhai, Elliot Chartash, Konstantin Dobrenkov, Joohyuk Sohn. Phase 1 evaluation of triple therapy with boserolimab (anti-CD27 agonist), pembrolizumab, and chemotherapy in patients with triple-negative breast cancer (TNBC) with PD-L1 combined positive score (CPS) <10: Safety, antitumor activity, and association between biomarkers and response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT095.

The Revolt of the Crew of De Zeven Provincien and the Activities of the National Movement of 1930-1933

World history records that at the end of 1920, the global community was hit by a very dramatic economic depression, which resulted in protests by the people as a result of cuts in the wages of civil servants in all circles, both Dutch and Indigenous nationalities, by 17%, wage cuts were part of the efforts government to reduce the gap between government revenues and spending when the economic depression has caused government revenues in an emergency. The relationship between the rebellion of the Crew of De Zeven Provincien and the activities of the national movement during the reign of Governor-General Jhr. B.C. De Jonge. After the uprising immediately, the Dutch East Indies government, under the leadership of Governor-General Jhr. B.C. De Jonge carried out reactionary and violent politics against the activities of the national movement. Movement organizations were increasingly under pressure from the colonial government, and some radical and revolutionary movement figures were even arrested. The research method used is the historical method, namely heuristics, source criticism, interpretation, and historiography, and this research uses library research where the researcher examines several sources related to this research. Thus, it can be concluded that in the De Zeven Provincien Crew Mutiny in 1933, Governor General Jhr. B.C. De Jonge put more pressure on the national movement organization in Indonesia.

Teaching-learning in clinical education based on epistemological orientations: A multi-method study.

Teaching-learning is the heart of medical education in the clinical setting. The objective of this research was to develop a conceptual model of effective clinical teaching in undergraduate medical education and conceptualize its operational framework based on the best fit approach. This research consisted of three sub-studies conducted using a multi-method approach. The first sub-study was conducted using a qualitative meta-synthesis approach. The second sub-study used Clarke's situational analysis approach as a postmodern version of grounded theory. Finally, the third sub-study was designed in two stages. First, it was conducted using the expert panel, in the second step, framework of synthesis based on best fit, and the framework of Ottenhoff- de Jonge et al., which formed the basis of this study. In the first sub-study, qualitative evidence on the factors of effective teaching-learning in clinical education was synthesized into five dimensions. Based on the second sub-study, the clinical teaching-learning situation in undergraduate medical education in Iran was represented in three maps, including situational, social worlds/arenas, and positional. Finally, in the third sub-study, based on model modification and development in the expert panel, the effective teaching-learning dimensions were developed into behavioral, social, pedagogical, technology, contextual, educational leadership, and financial dimensions. In the second step, based on the framework of Ottenhoff- de Jonge et al., a three-dimensional matrix was developed concerning epistemological orientations about teaching and learning. Moving from a single teaching-centered and learning-centered orientation to a teaching-learning-centered orientation is required for effective teaching-learning in clinical medical education.

Agricultural Activities and the Madura Salt Industry in the Late 19th Century to the 1930s

The colonial government's strong reason for continuing to pay special attention and evaluation to Madura was due to economic factors, namely the potential for large people's salt production and the potential for people's agriculture. The agrarian life for the Madurese has become a general trend, as is widely adopted in the economic system of the Indonesian people. This is evidenced by the fact that since the 17th century, Madura as a conquered area of the Mataram king Sultan Agung had the obligation to submit taxes every year in the form of one real, 10 pikul of rice and several pikul of fruit. This was corroborated by De Jonge who stated that until the next century the Madurese who still made a living as farmers included the majority of the population, namely around 70% - 80% of the total population, while the rest made a living as fishermen, even though this work actually required requirements. capital intensive. There is also the habit of the population to migrate out of the region, especially to plantation areas in Java as a workforce whose existence is clearly needed by plantation companies.

In Search of Identity: The Hadhrami Arabs in the Netherlands East Indies and Indonesia (1900–1950) , by Huub de Jonge

In Search of Identity: The Hadhrami Arabs in the Netherlands East Indies and Indonesia (1900–1950) , by Huub de Jonge

Prevention of surgical site infections: a personal odyssey

Prevention of surgical site infections: a personal odyssey

Variation in Incidence of Pneumothorax Complications After Percutaneous Lung Biopsies Among Veterans Health Administration Hospitals

Variation in Incidence of Pneumothorax Complications After Percutaneous Lung Biopsies Among Veterans Health Administration Hospitals

Facades-as-a-Service: Systemic managerial, financial, and governance innovation to enable a circular economy for buildings. Lessons learnt from a full-scale pilot project in the Netherlands

Introduction: The challenge of the energy transition in the built environment has, in recent years, been exacerbated by rising awareness of the material resource limitations we face on the path towards sustainable development. In this context the concepts of Circular Economy (CE) and Product-Service Systems (PSS) have emerged as potentially complementary industrial and business strategies to overcome the interdependent material resource and clean energy challenges.Research significance: Research in the field of circular and PSS-based construction frequently centres on the design and engineering of products, mainly through technical strategies such as design for disassembly and adaptability, and the use of the different “R’s” (Reuse, Repair, Remanufacturing, etc.) to extend and/or reset the service lives of building materials and components. Such an approach often ignores the fact that these strategies require changes in the management, financing, and governance aspects of products and therefore buildings, throughout their entire service-lives. This paper will focus on the systemic administrative (i.e. management, financing, and governance) challenges of the circular and servitisation transitions in the building and construction sector, to enable products which are “Circular by Design”, to effectively support regenerative processes.Research question: The paper asks how traditional building products’ management, financing, and governance processes prevent or delay the implementation of CE and PSS models. It explores the demand side’s perspective (commissioners, building owners and facility managers), taking a systemic view to the search for new practical, strategic, and scalable administrative models.Methodology: The research method applies the DAS model (De Jonge et al., 2009; Van der Zwart et al., 2009; den Heijer, 2011; den Heijer et al., 2016) to data gathered from focus group discussion and co-design sessions involving multidisciplinary teams of experts from both academy and industry, as well as literature. The research was conducted within the context of the TU Delft Facades-as-a-Service full-scale pilot project.Results: The research has shown that, while PSS models to enable material circularity can be partially implemented within the current managerial, financial, and governance framework, this implementation is not efficient, effective, or scalable. This is because standard modes of operation in these disciplines are misaligned with that goal. The practical barriers resulting from this misalignment increase the complexity, risk perception, and therefore cost of PSS alternatives, and thus prevent their organic adoption despite increasing market interest. Recommendations are made for policymakers, financiers, suppliers, and building owners to overcome these barriers.

Abstract 2137: Clinical utility of circulating tumor DNA in patients with advanced KRAS G12C-mutated NSCLC treated with sotorasib

Abstract Introduction: The CodeBreaK 200 trial showed that in patients (pts) with advanced KRAS G12C mutated (KRAS+) NSCLC sotorasib, a KRAS G12C-specific inhibitor, is superior to docetaxel for progression free survival (PFS) (HR 0.66) with a one-year PFS of 25%. We hypothesized that the detection of circulating tumor DNA (ctDNA) in plasma could allow for treatment response prediction and longitudinal monitoring. We analyzed serial plasma samples at baseline and within 3 months of start of sotorasib to evaluate ctDNA changes and correlation with clinical response. Methods: Pts with sotorasib treated KRAS+ NSCLC were prospectively enrolled in our biomarker START-TKI study (NCT05221372) after written informed consent. Plasma samples were collected prior to treatment (T0) and at first response evaluation (T1). The TruSight Oncology 500 ctDNA panel was used for mutation detection in cell-free DNA (cfDNA). cfDNA KRAS/TP53/STK11/KEAP1 status was determined and compared to tumor tissue pathology reports to filter out false positives. Radiological response and PFS was assessed per RECIST 1.1. Results: Between May 2021 and August 2022, 35 pts were included (table 1). Of these, 29 (83%) had detectable ctDNA KRAS G12C at T0, and 24 had both T0 and T1 samples. A decrease in variant allele frequency (VAF) at T1 compared to T0 was observed in 88% (n=21); 42% (n=10) showed complete clearance of ctDNA KRAS G12C. Six-months PFS was 83% in T0 negative pts (n=6) versus 43% in T0 positive pts (n=29); and 65% in pts with complete clearance (n=10) versus 14% in pts with incomplete clearance (n=11). VAF increase was seen in 3 pts, of which 1 had progression at T1. Conclusions: In pts with KRAS+ NSCLC treated with sotorasib, baseline ctDNA and ctDNA clearance within 3 months of treatment correlated with treatment response. Pts with undetectable KRAS ctDNA at baseline, or with complete clearance at first evaluation, had superior PFS. PFS will be updated as follow-up duration extends. Table 1. Patient cohort Liver metastasis KRAS p.G12C ctDNA at T0, median VAF % (range) KRAS p.G12C ctDNA at T1, median VAF % (range) Median change in VAF % (range) TP53/STK11/KEAP1 ctDNA T0 T1 response Reason EOT ꝉ Time on treatment (months) * Negative at T0 (n=6) No = 6 0 NE NE NE 1x PR; 4x SD; 1x PD 2x PD; 4x ongoing >8 months 6 (1 - 11) Positive at T0 (n=29) No = 20; Yes = 9 2.6 (0.1 - 46.7) 0.6 (0.1 - 38.9) -95% (-100 - +39) 4x TP53; 2x STK11; 1x STK11●; 2x KEAP1; 2x KEAP1●; 2x TP53 + KEAP1; 1x TP53 + STK11● 4x PR; 21x SD; 2x PD; 2x NE 19x PD; 3x toxicity; 6x ongoing >4 months; 1x loss to follow up 3 (1 - 15) Complete clearance at T1 (n=10) No = 6; Yes = 4 1.4 (0.1 - 8.4) 0 100% 2x TP53; 1x TP53 + KEAP1; 1x KEAP1; 1x KEAP1● 1x PR; 9x SD 6x PD; 1x toxicity; 2x ongoing >6 months; 1x loss to follow up 5 (1 - 11) Incomplete clearance at T1 (n=11) No = 7; Yes = 4 3.6 (1.3 - 46.7) 0.4 (0.1 - 29.4) -89% (-23 - -99) 2x TP53; 1x STK11; 1x STK11●; 2x TP53 + STK11●; 1x TP53 + STK11 + KEAP1; 1x STK11 + KEAP1 3x PR; 7x SD; 1x PD 8x PD; 2x toxicity; 1x ongoing >4 months 3 (1 - 8) Increase in VAF at T1 (n=3) No = 2; Yes = 1 1.0 (0.5 - 35.2) 1.1 (0.6 - 38.9) +11% (+10 - +39) 1x TP53●; 1x TP53 + KEAP1; 1x STK11● + KEAP1● 1x PD; 2x SD 3x PD 3 (1 - 15) Positive T0, no T1 available (n=5) No = 5 6.2 (0.3 - 24.6) NE NE 1x TP53; 1x TP53●; 1x KEAP1; 1x STK11 + KEAP1 3x SD; 2x NE 2x PD; 3x ongoing >3 months 2 (1 - 3) NE = Not evaluated; ● = Positive cell-free DNA (cfDNA), not tested in tumor tissue; PR = Partial response; SD = Stable disease; PD = Progressive disease; EOT = End of treatment; ꝉ for PFS analysis patients who discontinued treatment due to toxicity were censored at treatment discontinuation, and patients with ongoing sotorasib treatment were censored at data cut off (16-Nov-2022); * = excluding ongoing patients. Citation Format: Sophie M. Ernst, Ronald van Marion, Peggy N. Atmodimedjo, Evert de Jonge, Ron H. Mathijssen, Marthe S. Paats, Peter de Bruijn, Ron H.N. van Schaik, Hendrikus J. Dubbink, Anne-Marie C. Dingemans. Clinical utility of circulating tumor DNA in patients with advanced KRAS G12C-mutated NSCLC treated with sotorasib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2137.

Effects of a training intervention tailored to the menstrual cycle on endurance performance, recovery and well-being in female recreational runners – A randomized-controlled pilot study

Effects of a training intervention tailored to the menstrual cycle on endurance performance, recovery and well-being in female recreational runners – A randomized-controlled pilot study

Surveying citizens on food safety

Surveying citizens on food safety

Abstract 4018: Long-term response to Trastuzumab in patients with advanced gastric or gastroesophageal adenocarcinoma - A retrospective study

Abstract Since 2010, Trastuzumab combined with chemotherapy is the standard treatment for patients with HER2 (ERBB2) positive advanced or metastatic gastric and gastroesophageal junction cancer (GGEJ). While few patients show long-term response to the treatment, most suffer from rapid disease progression. Several studies revealed that genomic alterations, gene expression changes and altered HER2 signaling activity contribute to impaired therapy response. However, the underlying mechanism remains unclear. The aim of this research project is to analyze differences between patients with long and short progression-free survival by utilizing combined genetic, histologic, clinical and gene expression data. We collected a retrospective German patient cohort (n=20) including patients with HER2 positive advanced GGEJ who received Trastuzumab combined with chemotherapy. Using archival samples that were obtained prior to Trastuzumab treatment, we created a dataset including clinical information, histologic assessment, immunostaining, target amplicon sequencing (TAS; 409 gene panel) and human transcriptome data using the Affymetrix platform. To analyze the TAS sequencing data, we generated an automated analysis pipeline, which detects single nucleotide variants (SNV) and copy number alterations (CNA). Information about genomic alteration will be correlated with pathway and gene set enrichment analysis (GSEA) from the Affymetrix data. Furthermore, the data will be supported by investigating the functional status of HER2 in patient samples via electron microscopy. The results of this study could give insights on how genetic and transcriptomic alterations are connected to long-term Trastuzumab therapy response in HER2 positive GGEJ patients. This could potentially support therapy decision in personalized medicine. Citation Format: Isabel Porth, Philip Weidner, Sylvie Lorenzen, Wilko Weichert, Thorsten Oliver Götze, Sven Perner, Kim Luley, Daniela Hirsch, Ralf-Dieter Hofheinz, Diana B. Peckys, Zahra Mostajeran, Niels de Jonge, Timo Gaiser. Long-term response to Trastuzumab in patients with advanced gastric or gastroesophageal adenocarcinoma - A retrospective study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4018.

Abstract CT514: A phase I, open-label, dose-escalation study investigating a low-density lipoprotein receptor-related protein (LRP) 5/6 inhibitor, BI 905677, in patients with advanced solid tumors

Abstract Background: Ligand-dependent Wnt signaling, mediated by LRP5/6, is highly activated in a subset of solid tumors. Activation leads to accumulation of intracellular β-catenin and expression of β-catenin-dependent genes that promote cancer cell proliferation and treatment resistance. BI 905677 is a bi-paratopic antibody that binds LRP5/6 and blocks binding of Wnt ligands. This study (NCT03604445) aimed to identify the maximum tolerated dose (MTD) and determine the recommended dose for BI 905677 in patients with advanced solid tumors. Pharmacokinetics and efficacy will also be evaluated. Methods: This is a Phase I, open-label, non-randomized study of BI 905677, administered intravenously, in patients with advanced, unresectable and/or metastatic solid tumors. Patients were refractory to or not eligible for standard therapy. Patients were treated at increasing intravenous doses of BI 905677 (0.05, 0.1, 0.2, 0.4, 0.8, 1.6, 2.4, 2.8 and 3.6 mg/kg every 3 weeks [q3w]) until progression. Subsequent patients within a cohort were treated ≥ 72 hours apart to allow adequate monitoring for cytokine release syndrome and implementation of preventive measures if required. Results: As of November 23, 2021, 37 patients have received BI 905677. The median age was 56 years (range 32-77) and most were male (65%) and had ECOG PS 1 (51%). At 3.6 mg/kg, 3/3 patients experienced dose-limiting toxicities (DLTs) and dose was reduced to 2.8 mg/kg, which was determined as the MTD. Patients received a median of 2.0 cycles (range 1-6). Across all dose levels, 19 patients (51%) experienced Grade ≥ 3 adverse events (AEs). The most common Grade ≥ 3 AEs were vomiting (11%), hyponatremia (8%), anemia (5%), diarrhea (5%), abdominal pain (5%), nausea (5%), hypokalemia (5%), pain (5%) and increased alkaline phosphatase (5%). No related Grade ≥ 3 AEs were reported for doses ≤ 1.6 mg/kg, and BI 905677 was considered well tolerated ≤ 2.8 mg/kg. There were two Grade 5 events not related to study drug (tumor lysis syndrome and disease progression). DLTs observed at 3.6 mg/kg were hyponatremia, increased β-CTX expression (> 2-fold versus baseline), diarrhea, hyperbilirubinemia and vomiting. Exposure to BI 905677 increased in an approximately dose-proportional manner over the complete dose groups tested. No drug accumulation between Cycle 1 and Cycle 2 was observed for any cohort. Only six patients presented with anti-drug antibodies (ADAs), including one with pre-existing ADAs. Axin2 expression by reverse transcription PCR was reduced in paired skin biopsies but no dose dependency was observed. Across all doses, the best response was stable disease (n = 13; 35%). Conclusions: BI 905677 was well tolerated, with the MTD established as 2.8 mg/kg q3w. An expansion cohort to evaluate the activity of BI 905677 in a molecularly selected population for Wnt ligand dependence is planned. Citation Format: Elena Élez, Heinz-Josef Lenz, Maja de Jonge, Rona Yaeger, Toshihiko Doi, Linda Pronk, Michael Teufel, Kristell Marzin, Josep Tabernero. A phase I, open-label, dose-escalation study investigating a low-density lipoprotein receptor-related protein (LRP) 5/6 inhibitor, BI 905677, in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT514.

1415-P: Risk–Benefit Data from the Worldwide EndoBarrier (EB) Registry

Uncertainty exists re risk:benefit of proximal intestinal exclusion with EB, a novel endoscopic duodenal jejunal liner device for obesity, both with and without diabetes. In view of this, during 2017, an independent, secure, on line registry was established under the auspices of the Association of British Clinical Diabetologists, for the collection of safety and efficacy data worldwide. As of December 2021, data had been entered on 10patients {age 52.1 ± 10.3 year, 53% male, 87% diabetes, BMI 41.1 ± 8.9 kg/m2} and showed many benefits (Table 1) . There were 43 (4.2%) SAEs and 139 (13.9%) less serious AEs (Table 2) . All SAE patients made a full recovery and most derived significant benefit. The benefits of EB therapy are likely to reduce the complications of diabetes. This international data from the EB registry suggests that the likely benefits of EB, far outweigh the risks Disclosure R.E.J. Ryder: None. J.P. Teare: None. A. Ruban: None. M. Haluzik: Advisory Panel; Boehringer Ingelheim International GmbH, Novo Nordisk A/S, Sanofi. Speaker's Bureau; Abbott Diabetes, AstraZeneca, Lilly Diabetes, Novartis AG. L. Munro: None. H. Frydenberg: None. J.J. McMaster: None. S. Fishman: None. R.V. Cohen: Advisory Panel; GI Dynamics. Research Support; Johnson & Johnson, Medtronic. C.M. Aboud: None. G.J. Holtmann: Research Support; AbbVie Inc., Allergan, Arena Pharmaceuticals, Inc., Bayer, Bristol Myers, Datapharm Australia Pty Ltd Commonwealth Laboratories, Pty Limited, Eli Lilly Australia Pty Limited, F.Hoffmann-La Roche Limited, Falk Foundation, Falk GmbH and Co Kg, GI Therapies Pty Ltd, Gilead Sciences Pty Limited, MedImmune Ltd Celgene Pty Limited, Mylan, Nestle Pty Ltd, Prometheus Laboratories, Quintiles Pty Limited, Servatus, Takeda Development Center Asia, Pty Ltd, Vital Food Processors Ltd. C. de Jonge: None. J. Greve: Advisory Panel; GI Dynamics. Other Relationship; Bariatric Solutions International, Ethicon, Inc. J.C. Mason: None. H. Sourij: Advisory Panel; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Daiichi Sankyo, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk. Research Support; Boehringer Ingelheim International GmbH, Sanofi. Speaker's Bureau; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novartis AG, Novo Nordisk. R. Drummond: Research Support; Fractyl Health, Inc. Speaker's Bureau; AstraZeneca, Bristol-Myers Squibb Company. B. McGowan: Advisory Panel; Johnson & Johnson, Lilly, Novo Nordisk. Research Support; Novo Nordisk. Speaker's Bureau; AstraZeneca, Novo Nordisk. Stock/Shareholder; Reset Health. S.A. Amiel: Advisory Panel; Medtronic, Novo Nordisk. Other Relationship; Sanofi. M. Yadagiri: None. P. Sen Gupta: None. K. Laubner: None. J. Seufert: Advisory Panel; Abbott, Sanofi-Aventis Deutschland GmbH. Research Support; Boehringer Ingelheim International GmbH. Speaker's Bureau; Abbott Diabetes, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. Funding Association of British Clinical Diabetologists

AN ESCAPE FROM VARDANYAN’S THEOREM

AbstractVardanyan’s Theorems [36, 37] state that $\mathsf {QPL}(\mathsf {PA})$ —the quantified provability logic of Peano Arithmetic—is $\Pi ^0_2$ complete, and in particular that this already holds when the language is restricted to a single unary predicate. Moreover, Visser and de Jonge [38] generalized this result to conclude that it is impossible to computably axiomatize the quantified provability logic of a wide class of theories. However, the proof of this fact cannot be performed in a strictly positive signature. The system $\mathsf {QRC_1}$ was previously introduced by the authors [1] as a candidate first-order provability logic. Here we generalize the previously available Kripke soundness and completeness proofs, obtaining constant domain completeness. Then we show that $\mathsf {QRC_1}$ is indeed complete with respect to arithmetical semantics. This is achieved via a Solovay-type construction applied to constant domain Kripke models. As corollaries, we see that $\mathsf {QRC_1}$ is the strictly positive fragment of $\mathsf {QGL}$ and a fragment of $\mathsf {QPL}(\mathsf {PA})$ .

Calorie restriction and calorie dilution have different impacts on body fat, metabolism, behavior, and hypothalamic gene expression.

Caloric restriction is a robust intervention to increase lifespan. Giving less food (calorie restriction [CR]) or allowing free access to a diluted diet with indigestible components (calorie dilution [CD]) are two methods to impose restriction. CD does not generate the same lifespan effect as CR. We compare responses of C57BL/6 mice with equivalent levels of CR and CD. The two groups have different responses in fat loss, circulating hormones, and metabolic rate. CR mice are hungrier, as assessed by behavioral assays. Although gene expression of Npy, Agrp, and Pomc do not differ between CR and CD groups, CR mice had a distinctive hypothalamic gene-expression profile with many genes related to starvation upregulated relative to CD. While both result in lower calorie intake, CR and CD are not equivalent procedures. Increased hunger under CR supports the hypothesis that hunger signaling is a key process mediating the benefits of CR.

‘Those who laugh as a body today, will march as a body tomorrow’: Critical comedy and the politics of community

Comedians are often celebrated for critically confronting their audiences, thereby upsetting deep-held beliefs of spectators and contributing to progressive change. In this article, I will use Dutch comedy as my case study to demonstrate that comedians’ playful opposition to the audience has serious political implications and reveals a deep suspicion towards political community. By analysing this fear of the community, this article contributes to a better understanding of the politics of comedy and challenges the dominant idea that critical comedy is inherently progressive and emancipatory. I point to the separate ways in which two Dutch comedians from different generations – Freek de Jonge and Micha Wertheim – use humour to unmask the audience as proto-fascist mass.

Freedom’s Dominion: A Saga of White Resistance to Federal Power by Jefferson Cowie

Reviewed by: Freedom’s Dominion: A Saga of White Resistance to Federal Power by Jefferson Cowie Greta De Jong (bio) Freedom’s Dominion: A Saga of White Resistance to Federal Power. By Jefferson Cowie. (New York: Basic Books, 2022. Pp. x, 497. $35.00 cloth; $19.99 ebook) Jefferson Cowie provides a comprehensive and timely analysis of white racists’ longstanding antipathy toward the federal government in this book. In recent decades, scholars such as Joseph Crespino, Kevin Kruse, and Matthew Lassiter have examined connections between antigovernment beliefs and opposition to racial equality that were evident in the mid-twentieth century as white southerners mobilized to fight the enforcement of civil rights legislation. Similarly, Kathleen Belew has shown how white supremacist ideologies motivated antigovernment groups and domestic terrorism after the 1960s. Cowie extends the story back in time, arguing that for most of the history of the United States—from settler colonialism to Trumpism—attacks on federal “tyranny” and resistance to government power aimed to preserve white Americans’ freedom to oppress other people. Cowie uses developments in the town of Eufaula in Barbour County, Alabama, to trace the evolution of what he calls “racialized anti-statism” through four key periods in the nation’s history: the dispossession and removal of Indigenous people from their lands; the violent destruction of interracial democracy during Reconstruction; [End Page 201] the license to murder provided to white southerners during the Jim Crow era; and the nationalized opposition to government action on behalf of racial and economic justice in the late twentieth century (p. 5). In each case, antigovernment rhetoric and calls to defend “freedom” were used to justify actions that only protected the ability of some Americans to deny freedom and democracy to others. Conflicts over the enforcement of the Treaty of Cusseta in the 1830s provide an early instance where arguments over federal power, states’ rights, and white freedom emerged and were resolved on the side of white dominance. Armed white invaders illegally squatting on Creek land refused to abide by the law and violently resisted the federal agents sent in to remove them. The deaths that resulted and accusations that the government’s actions amounted to “tyranny” weakened the resolve of U.S. forces, and they eventually abandoned their efforts, setting the pattern for later interventions. Creek dispossession allowed the rise of a slaveholding economy where white freedoms were based on extreme exploitation and abuse of African Americans. When this system was destroyed and Black people gained citizenship rights during Reconstruction, white supremacists mobilized to cast the experiment in interracial democracy as an illegitimate form of coerced equality that they were justified in overthrowing through fraud and violence. The federal government’s withdrawal of support for racial equality helped to usher in the Jim Crow era, when adherence to the doctrine of states’ rights meant white southerners could cheat, imprison, beat, maim, and kill Black southerners with impunity. Despite the civil rights movement’s success in ending legalized racial discrimination in the 1960s, angry white resistance and the resurgence of racialized anti-statism once again undermined federal efforts to fully enforce civil rights laws. Cowie’s analysis is persuasive and supported by evidence drawn from government records, the papers of political leaders and activists, presidential speeches, oral histories, and other archival sources. The book’s most important contribution is its powerful demonstration of [End Page 202] the need for the federal government to play a forceful role in expanding the definition of freedom beyond the narrow vision of those who think it means the unrestrained ability to dominate others. Greta De Jong GRETA DE JONG is a professor of history at the University of Nevada, Reno. Her most recent book is You Can’t Eat Freedom: Southerners and Social Justice after the Civil Rights Movement (2016). Copyright © 2022 Kentucky Historical Society