Van Der Vegt Research Articles

Abstract PO2-13-03: Spatial HER2 heterogeneity on HER2-PET in HER2-low and negative disease: potential biomarker for antibody-drug conjugate effect

Abstract Background: Anti-HER2 antibody drug conjugates (ADCs) can assert an effect in part of patients with HER2-low breast cancer. In light of patient burden and financial sustainability, biomarkers to select responding patients are urgently needed, but so far, none have been identified. In the IMPACT trial (NCT01957332), patients with newly diagnosed and non-rapidly progressive metastatic breast cancer (MBC) of all subtypes (including HER2-negative, -low, and –positive disease) were included. We assessed the performance of Zirconium-89 (89Zr)-trastuzumab positron emission tomography (HER2-PET) in HER2-low and negative MBC. Methods: All patients received extensive workup, including a metastasis biopsy and HER2-PET at baseline. HER2 status was determined by immunohistochemistry (IHC) and in situ hybridization. ⁸⁹Zr-trastuzumab uptake was quantified as maximum and mean standardized uptake values (SUVmax, SUVmean) in metastases and healthy background tissue. Quantitative ⁸⁹Zr-trastuzumab uptake of all metastases and corresponding biopsied metastasis, was related to HER2 IHC status. Results: In 200 patients, ⁸⁹Zr-trastuzumab uptake was quantified in 5,163 metastases. With increasing HER2 IHC status, uptake was higher (geometric mean SUVmax 7.0, 7.6, 7.3, and 17.4 with HER2 IHC 0, 1, 2, or 3+, in respectively 71, 71, 20, and 24 biopsied metastases (P  0.001 between IHC 0 and 3+). SUVmax in lesions was heterogeneous within and between patients for all HER2 IHC groups. All HER2 IHC groups, also HER2-negative and -low, had uptake exceeding that of the healthy background (geometric mean tumor-to-background ratio SUVmax >1 in all groups, increasing with higher HER2 IHC). Of patients with a HER2 IHC 0 biopsy, 27.8% had at least one metastasis elsewhere in the body, with uptake exceeding the overall 90th SUVmax percentile of 14.6; in HER2 low IHC1+ and 2+, this was 31.9% and 30%. Conclusions: In this largest series with HER2-PET in patients with MBC, we show that ±30% of patients with HER2-low or -negative IHC in the biopsy, in fact, have metastases with high HER2 uptake elsewhere in the body. This spatial heterogeneity provides novel insights into HER2-negative and -low disease compared to standard HER2 IHC of a single biopsy. As HER2-PET uptake is related to ADC response in HER2 positive MBC1, HER2-PET is a potential biomarker for anti-HER2 ADC effect in HER2-low and -negative MBC as well. Reference: 1. Gebhart G, et al. Ann Oncol 2016;27(4): 619-624. Supported by the Dutch Cancer Society grant 2012-5565 Citation Format: Carolien Schroder, Jasper van Geel, Bertha Eisses, Adrienne Brouwers, Sjoerd Elias, Frederike Bensch, Evelien Kuip, Agnes Jager, Andor Glaudemans, Bert van der Vegt, Willemien Menke-van der Houven van Oordt, Elisabeth de Vries. Spatial HER2 heterogeneity on HER2-PET in HER2-low and negative disease: potential biomarker for antibody-drug conjugate effect [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-13-03.

Mapping scheme as key element in coarse-graining of methacrylate-based polymers

Atomistic molecular modelling of polymeric hybrid materials becomes more relevant with continually increasing computing power. Currently, the simulations are still limited to medium size atomistic models, although polymer dynamics demand large polymer chain models and time scales. Coarse-graining of atomistic polymer models is aiming at the transfer of structure related properties from fully atomistic models to bead representations having less degrees of freedom but allowing the increase of model size and time scales. Key for a successful bead representation is the mapping scheme. Although there are a lot of meaningful approaches for polymer mapping schemes available (e. g. mapping one repeat unit to one bead), the successful development is not always a trivial task and every approach has advantages and shortcomings. Even for the rather “simple” polystyrene at least seven different and meaningful mapping scheme approaches are known (H. A. Karimi-Varzaneh, N. F. A. van der Vegt, F. Müller-Plathe, P. Carbone, ChemPhysChem2012, 13, 3428.).Here, we show the importance of the mapping scheme for a more sophisticated hybrid material substance and evaluate its quality, i. e. speedup and atomistic model representation by the coarse-grained models. The degree of coarse-graining of different mapping schemes is discussed. The coarse-grained models are evaluated according to their glass transition analysis in comparison to the full atomistic glass transition analysis. It is shown, that the choice of the mapping scheme becomes more crucial with increasing monomer complexity. Finally, the trade-off between efficiency, i. e. time-saving with speed-up during simulation vs. time-loss for coarse-grained force field parameter development, and quality of results, i. e. comparability with fully atomistic models, has to be considered carefully.

Building responsive and resilient supply chains: Lessons from the COVID‐19 disruption

Building responsive and resilient supply chains: Lessons from the <scp>COVID</scp>‐19 disruption

Decision-making in the Context of a Crisis: A Selected Review

In the 21st century, organisations have to face pressing “big challenges” (George et al., 2016). These can include adverse events such as global pandemics and climate change. The impacts of these adverse events lead organisations and decision-makers to adopt new behaviours. Although these adverse events are inevitable, organisations do not respond in the same ways, and some organisations are better able to withstand and recover from such shocks than others (Van der Vegt et.al, 2015). High-risk events that at first appear to cause only local and isolated effects, can multiply in intensity and damage vital infrastructure, affecting events on a national or global scale. McFarlane and Norris (2006, p. 4) defined an adverse event as “a potentially traumatic event that is experienced collectively, has an acute onset, and is limited in time; it can be attributed to natural, technological or human causes”. An adverse event is caused by factors external to the system, unforeseen, and requiring immediate action. Examples include hurricanes, tsunamis, earthquakes and pandemics. The traditional way of dealing with adverse events is to develop approaches and systems to identify risks. Now, scholars are shifting their attention from identifying and mitigating risk to attempting to increase resilience (Sutcliffe & Vogus, 2003). The term “resilience” almost always has the positive connotation of flexibility and strengthening: The desired result is better than the preparation needed to face disruptive unexpected events. The purpose of this study is to understand the impact of strategic choices in response to adverse events on the life of organisations. Specifically, when their responses to adverse events occur in a non-adaptive or non-resilient way (inertia). In order to understand this, we based this study on a review of the literature specifically linke.

Relationships and Resilience in the COVID-19 Pandemic

Society, organizations, and individuals inevitably face crises that threaten their functioning and even survival. As a result, crisis management scholars have sought to explain both the nature and impact of crises and how organizations effectively prepare for, respond to, and overcome various forms and degrees of challenges (Williams, Gruber, Sutcliffe, Shepherd, & Zhao, 2017). In response to a rise of grand challenges (e.g., Covid-19 pandemic), there have been a number of calls for management research to further explore the crisis-organization interaction, including how to develop resilience not only to respond to adversity but also to use it as an opportunity for future growth (van der Vegt, Essens, Wahlström, & George, 2015; Williams & Shepherd, 2016). Following this, our symposium aims to provide a unique and critical perspective that focuses on relational practices as the approach to address grand challenges as well as the relational capability to respond to and recover from adversity. In the context of crisis management, relational practice has been considered an important approach to shape immediate response to disturbances and ultimately enhance reliability to challenging events (Williams et al., 2017). For example, Gittell (2008) found that relational coordination—communicating and relating for the purpose of task integration—is critical in overcoming challenges. The coordinated collective response across multiple functions or roles create a relational system that enables and strengthens resilient responses to external pressures. Similarly, Shepherd and Williams (2014) and Colquitt et al. (2011) found that trust is an elemental capability to enable a more effective response to a disaster. Use of Incident Command System to Improve Relational Capacity Among Providers Presenter: Lauren Hajjar; Suffolk U. Presenter: Julius Yang; Beth Israel Lahey Telehealth for Coordinating Between Patients, Families, and Care Providers during COVID-19 Presenter: Ben Kragen; Brandeis U. Clinician Resilience During COVID: The Role of Work-Life Balance and Relational Coordination Presenter: Heba Naim Ali; Brandeis U. Presenter: Jody Hoffer Gittell; Brandeis U. Presenter: Sien Deng; Palo Alto Medical Foundation Research Institute Presenter: Cheryl Stults; Palo Alto Medical Foundation Research Institute Presenter: Meghan Martinez; Palo Alto Medical Foundation Research Institute Presenter: Suzanne Pertsch; Palo Alto Foundation Medical Group Presenter: Lauren Weger; Palo Alto Foundation Medical Group Presenter: Ellis Dillon; Palo Alto Medical Foundation Relationships and Resilience: How a Major Canadian Tertiary Care Center Responded to the Pandemic Presenter: Samer Faraj; McGill U. Presenter: Anand Bhardwaj; McGill U. - Desautels Faculty of Management Presenter: Kathy Malas; CHUM Research Centre

Cross-correlation corrected friction in generalized Langevin models: Application to the continuous Asakura-Oosawa model.

The development of dynamically consistent coarse-grained models for molecular simulations is often based on generalized Langevin equations, motivated by the application of the projection operator formalism (Mori-Zwanzig theory). While Mori's projection operator yields linear generalized Langevin equations that can be computationally efficiently implemented in numerical simulations, the downside is that Mori's generalized Langevin equation does not encompass the multi-body potential of mean force required to correctly encode structural and thermodynamic properties in coarse-grained many-body systems. Zwanzig's projection operator yields nonlinear generalized Langevin equations including the multi-body potential of mean force, while the remaining force contributions are not as cheap to implement in molecular simulation without making it formally hard to justify approximations. For many-particle coarse-grained models, due to computational and conceptual simplicity, an often used approach is to combine nonlinear conservative interactions with linear expressions to model dissipation. In a previous study [V. Klippenstein and N. F. A. van der Vegt, J. Chem. Phys. 154, 191102 (2021)], we proposed a method to parameterize such models to achieve dynamic consistency in coarse-grained models, allowing us to reconcile Mori's and Zwanzig's approach for practical purposes. In the current study, by applying the same strategy, we develop coarse-grained implicit solvent models for the continuous Asakura-Oosawa model, which under certain conditions allows us to develop very accurate coarse-grained potentials. By developing coarse-grained models for different reference systems with varying parameters, we test the broader applicability of the proposed procedure and demonstrate the relevance of accurate coarse-grained potentials in bottom-up derived dissipative models. We study how different system parameters affect the dynamic representability of the coarse-grained models. In particular, we find that the quality of the coarse-grained potential is crucial to correctly model the backscattering effect due to collisions on the coarse-grained scale. As hydrodynamic interactions are not explicitly modeled in the presented coarse-graining approach, deviations are observed in the long-time dynamics. The Asakura-Oosawa model allows for the tuning of system parameters to gain an improved understanding of this limitation. We also propose three new iterative optimization schemes to fine-tune the generalized Langevin thermostat to exactly match the reference velocity-autocorrelation function.

Abstract 6260: Identification of molecular imaging targets specific for head and neck squamous cell carcinoma by transcriptional adaptation to copy number alterations profiling: Digital data translated to protein expression

Abstract Objective: Head and neck squamous cell carcinoma (HNSCC) can intraoperatively be visualized by fluorescence molecular imaging (FMI) using fluorophores conjugated to HNSCC specific antibodies. Currently, the epidermal growth factor receptor (EGFR) is used as a target. Targets more specific for HNSCC would reduce background signal, resulting in a higher tumor to background ratio. We aimed to identify new potential targets for FMI in HNSCC. Methods: Publicly available transcriptomic data were collected. A biostatistical method known as Transcriptional Adaptation to Copy Number Alterations (TACNA) profiling was applied, which captures the downstream effects of copy number alterations (CNAs) on mRNA levels, which we used to predict the overexpression on the protein level. By comparing gene expression profiles of HNSCC and normal oral mucosa, genes overexpressed explicitly in HNSCC were identified. Potential targets were selected based on the degree of overexpression, plasma membrane expression, and cross expression in other tissues in the head and neck region. Next, the expression of potential targets of TACNA results on mRNA level were validated on the protein level and compared to EGFR expression using immunohistochemistry (IHC). Subsequently, paired biopsies of HNSCC, adjacent suspicious mucosa, and healthy mucosa of the same patients were stained. Receptor expression was evaluated using H-scores (i.e., percentage of positive cells combined with staining intensity). Results: TACNA profiling was applied on 111 samples of healthy oral mucosa and 410 HNSCC comparing expression levels of 19,635 genes. The newly identified membrane-bound targets were glucose transporter 1 (GLUT-1), placental cadherin (P-cadherin), and monocarboxylate transporter 1 (MCT-1). The three targets were evaluated by IHC in a total of 31 patients, of which 8 had oropharyngeal, 7 hypopharyngeal, and 16 laryngeal carcinomas. GLUT-1 had a median H-score of 175, P-cadherin 140, and MCT-1 40. GLUT-1 and P-cadherin were significantly higher compared to EGFR, with a median H-score of 90 (p &amp;lt; .001). GLUT-1 receptor expression was also seen on erythrocytes, while P-cadherin expression was seen in the basal layer of normal epithelium. This can complicate its use in FMI. Conclusion: TACNA profiling results were successfully validated in immunohistochemistry as a first step in the search for new specific FMI targets in HNSCC. GLUT-1 and P-cadherin show promising results with significantly higher receptor expression than EGFR. Citation Format: Jeroen E. van Schaik, Bert van der Vegt, Bernard F.A.M. van der Laan, Max J.H. Witjes, Sjoukje F. Oosting, Rudolf S. Fehrmann, Boudewijn E. Plaat. Identification of molecular imaging targets specific for head and neck squamous cell carcinoma by transcriptional adaptation to copy number alterations profiling: Digital data translated to protein expression [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 6260.

Abstract 6261: Comparison of glycoprotein nonmetastatic melanoma protein b, epidermal growth factor receptor and vascular endothelial growth factor expression in head and neck squamous cell carcinoma, and untreated and residual lymph node metastases

Abstract Objective: To evaluate expression of the potential molecular imaging targets glycoprotein nonmetastatic melanoma protein B (GPNMB) and vascular endothelial growth factor (VEGF) in comparison to classical epidermal growth factor receptor (EGFR) in previously untreated head and neck cancer primary tumors and corresponding lymph node metastases, and in lymph node metastases after initial (chemo)radiotherapy. Methods: Primary tumors and lymph node metastases of 38 patients who underwent primary resection of head and neck squamous cell carcinoma (HNSCC) were selected. In addition, lymph node metastases from salvage surgery after (chemo)radiotherapy from 22 patients with HNSCC were selected. Immunohistochemical staining for EGFR, VEGF and GPNMB was performed, after which protein expression was scored using H-scores (percentage of positive tumor cells multiplied by staining intensity ranging from 0 to 2). Primary tumors and lymph node metastases with an H-score ≥5 were considered positive, after which sensitivity rates were calculated. Groups were compared using the Mann-Whitney U test for non-parametric data with post-hoc Bonferroni corrections. Results: In untreated primary HNSCC the sensitivity was 86.8% for EGFR (median H-score 60), 92.1% for VEGF (median 60), and 100% for GPNMB (median 100). In previously untreated lymph node metastases the sensitivity was 81.6% for EGFR (median 30), 86.8% for VEGF (median 65), and 100% for GPNMB (median 118). In lymph node metastases after initial (chemo)radiotherapy, sensitivity was 86.4% for EGFR (median 95) and 100% for GPMB (median 100). VEGF sensitivity could not reliably be evaluated in these lymph nodes due to nonspecific staining in all tissue slides. GPNMB expression was significantly higher compared to EGFR in untreated primary HNSCC (p = .009 and p &amp;lt; .001, respectively) and lymph node metastases (p &amp;lt; .001 for both). Conclusion: GPNMB shows better tumor-specific receptor expression in both sensitivity and H-scores compared to EGFR and VEGF in immunohistochemistry. VEGF performed comparable to EGFR in untreated HNSCC and lymph node metastases. GPNMB could therefore be a new potential imaging target based on these immunohistochemical results. Citation Format: Jeroen E. van Schaik, Bert van der Vegt, Saskia H. Hanemaaijer, Gyorgy B. Halmos, Max J. Witjes, Bernard F.A.M. van der Laan, Rudolf S. Fehrmann, Sjoukje F. Oosting, Boudewijn E. Plaat. Comparison of glycoprotein nonmetastatic melanoma protein b, epidermal growth factor receptor and vascular endothelial growth factor expression in head and neck squamous cell carcinoma, and untreated and residual lymph node metastases [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 6261.

Abstract 5813: Glycogen synthesis as potential novel target in triple negative breast cancer: Glycogen synthase 1 expression in human breast cancers and the impact of downregulation on proliferation of preclinical models

Abstract Background: Triple-negative breast cancer (TNBC) has a poor clinical prognosis and is characterized by a lack of druggable targets and a hypoxic tumor microenvironment. Hypoxia-induced glycogen accumulation and utilization are involved in cancer proliferation and therapy resistance, making modulation of glycogen metabolism of therapeutic interest. Therefore, we studied expression of glycogen synthase 1 (GYS1, the key regulator of glycogen synthesis) and glycogen stores in publicly available expression data and human breast tumors including TNBC. Also, we studied downregulation of GYS1 in preclinical breast cancer models, focusing on TNBC. Methods: GYS1 mRNA expression and correlations with survival per clinical subtype were assessed in the METABRIC dataset. A tissue micro-array was constructed from primary tumors of 396 breast cancer patients with long-term follow-up, including normal breast control tissue. Triplicate tissue cores were stained immunohistochemically for GYS1, glycogen and the hypoxic marker carbonic anhydrase 9, and with periodic acid-Schiff staining for glycogen. In four TNBC cell lines and an MDA-MB-231 xenograft model, GYS1 protein expression, glycogen content and cell proliferation in normoxia and hypoxia were evaluated +/- GYS1 knockdown by siRNA or shRNA. Sensitivity of shGYS1 cell lines to drugs targeting mitochondria was tested. Results: In the METABRIC dataset (n = 1904), overexpression of GYS1 mRNA was associated with poor overall survival (HR 1.20 [95% CI 1.05 - 1.38]), which was mainly driven by the TNBC patients (n = 299, HR 1.52 [95% CI 1.09 - 2.14]). Immunohistochemically, most primary breast tumors had elevated GYS1 levels and glycogen content compared to normal breast tissue, with subtype specific analyses ongoing. In all breast cancer cell lines, hypoxia induced GYS1 protein expression and increased glycogen content. Acute siRNA-mediated GYS1 knockdown decreased proliferation of (TN)BC cell lines and MDA-MB-231 spheroids in both hypoxia and normoxia. shGYS1 MDA-MB-231 cells had decreased glycogen levels and shGYS1 MDA-MB-231 xenograft growth was impaired, especially in the first six weeks after inoculation. In control xenografts, immunohistochemical GYS1 expression was most pronounced adjacent to the necrotic tumor core, whereas shGYS1 xenografts lacked GYS1 expression. Finally, shGYS1 MDA-MB-231 cells were more sensitive to inhibitors of mitochondrial protein homeostasis, suggesting a potential synergistic approach to overcome eventual metabolic adaptation. Conclusions: GYS1 is overexpressed in primary breast tumors and high mRNA levels correlate with poor survival in TNBC. GYS1 downregulation impairs TNBC proliferation in vitro and in vivo, highlighting glycogen synthesis as potential novel therapeutic target in TNBC. Citation Format: Ellen C. De Heer, Christos E. Zois, Esther Bridges, Mieke C. Zwager, Tineke van der Sluis, Bert van der Vegt, Carolien P. Schröder, Steven de Jong, Adrian L. Harris, Mathilde Jalving. Glycogen synthesis as potential novel target in triple negative breast cancer: Glycogen synthase 1 expression in human breast cancers and the impact of downregulation on proliferation of preclinical models [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 5813.

Assessment procedures in anonymously written threats of harm and violence. Correction to van der Vegt et al. (2022).

Assessment procedures in anonymously written threats of harm and violence. Correction to van der Vegt et al. (2022).

The Development and Validation of a Cognitive Diversity Scale for Chinese Academic Research Teams.

Cognitive diversity is an important concept stemming from western management research in the 1990s. With the rapid development of science and technology, there is a growing interest in the composition of an academic research team, such as team diversity. However, there is no tool available for measuring team cognitive diversity (TCD) for academic research teams. Based on Van der Vegt’s theoretical model of TCD, an Academic Research Team Cognitive Diversity Scale (ATCDS) is developed and validated for an academic research team in our research with two studies (N=737). In Study One, in-depth interviews and panel discussions were conducted to generate a preliminary questionnaire. In Study Two, the questionnaire was administered among academic research teams. Exploratory factor analysis revealed four factors regarding cognitive diversity: (1) the way of thinking, (2) knowledge and skills, (3) the view of the world, and (4) beliefs about what is right and wrong. The factor structure was further validated by confirmatory factor analysis. Moreover, correlation and regression analyses showed that academic research TCD was positively related to team creativity (r =0.306, p <0.01) and performance (r =0.204, p <0.10). To sum up, our newly developed 15-item ATCDS is sufficiently reliable and valid to be used for understanding cognitive diversity among academic research teams.

Analysis of Polarization Curves of a Commercial Membrane With an Extract of Metal Ions from Soils Impacted with Mining Tailings

Polarization curves are obtained in cation exchange membranes (Neosepta CMX Tokuyama Co., Japan). The analysis allowed to determine the transition zone in which the depletion of the counterion in the diffusion layer occurs. The fixed charge of the membrane confers selective properties depending on the size of the mixture of ions extracted from the soil sample. The results of the limit current analysis in the membrane reflect the presence of a mixture of ions where the diffusion layer is altered [1-2]. The soils were obtained from mining tailings disposed of in the open pit in Guanajuato, Gto. Mexico. The extracts of the ion mixture were obtained by contacting the soil samples with 0.5 M magnesium chloride. The polarization curves were obtained from extracts digested in an acid medium and without this treatment. The digestion of the extracts was carried out to total dryness on a heating plate with a solution of HNO3 and resuspended to a volume of 25 mL. The polarization curves were obtained in a two-cell device made with acrylic tubes containing 25 mL of solution each.The CMX membrane was placed between the two cells by applying progressive potential with a power source to the working electrodes placed at the ends of the device. The potential difference was measured with a multimeter on two Ag / AgCl reference electrodes (3 M NaCl) placed on each side of the membrane. At the same time the current developed in the system was recorded. The polarization curves were constructed from the current and potential recorded in the multimeters. The results suggest that the diffusion layer is thinner in the reference soil. The high values of Ilim in the mining tailings show the presence of an important mixture of ions.[1] M. Garcia-Gabaldon, V. Perez-Herranz, E. Ortega., Evaluation of two ion-exchange membranes for the transport of tin in the presence of hydrochloric acid, J. Membr. Sci., 371 (2011) 65-74.[2] F.G. Wilhelm, N.F.A. van der Vegt, M. Wessling, H. Strathmann, Chronopotentiometry for the advanced current – voltage characterization of bipolar membranes, Journal of Electroanalytical Chemistry 502 (2001) 152–166.The authors assign the rights toThe Electrochemical Society Advancing Solid State & Electrochemical Science & Technology.

New Perspectives on Hierarchical Roles in Groups and Organizations: Beyond High Rank vs Low Rank

Research on hierarchy has exploded in recent years. In this work, management scholars have largely focused on high- and low- rank roles within a hierarchy and how high and low rank can drive individual, group, and organizational processes and outcomes. However, recent work has begun to move beyond the study of traditional high- versus low- rank roles in hierarchies to instead consider other consequential hierarchical roles in groups and organizations. In this symposium, we highlight this emerging area of research on alternative perspectives on hierarchical roles, bringing together a set of five cutting-edge papers. These papers all offer new perspectives on the roles of different hierarchical ranks, including developing theory on the role of various high-ranking members in alliances (first paper), unpacking the consequences of a common yet overlooked rank: the second-in-command rank (second paper), identifying how middle and low-ranking group members can emerge as informal leaders (third paper), challenging whether high ranks matter at all considering high rank does not automatically confer authority (fourth paper), and understanding the experience of rank ‘losers’ (fifth paper). The five papers across this symposium move beyond traditional studies of high- versus- low ranked roles in hierarchies and demonstrate that these other perspectives on hierarchical roles can also have profound influences on individual, group, and organizational processes and outcomes. Following the presentations, Dr. Drew Carton will facilitate a group discussion about these papers and future research on alternative views on hierarchical roles. Team Leadership Through an Inner Circle: How a Dominant Alliance Can Encourage Coordination and... Presenter: Jieying Xu; ZHEJIANG U. OF FINANCE AND ECONOMICS Presenter: Xu Huang; Hong Kong Baptist U. Presenter: Erica Xu; Hong Kong Baptist U. Presenter: Gerben S. Van Der Vegt; U. of Groningen Presenter: Stuart Bunderson; Wash U. Do Teams Need a Second Fiddle? The Opportunities (and Perils) of the Second-in-Command Rank in a... Presenter: Elizabeth Trinh; U. of Michigan, Ross School of Business Presenter: Lindred L. Greer; U. of Michigan, Ross School of Business Second in Command or Second Opinion? Testing a Dual-path Model of Informal Leader Emergence Presenter: Edward McClain Wellman; Arizona State U. Presenter: Min Yu; Arizona State U. Presenter: Luke Hedden; Boston College Presenter: Beth Schinoff; Boston College How Managers Produce Authority During Backstage Repair: Evidence From Flash Teams Presenter: Melissa Valentine; Stanford U. Presenter: Michael Bernstein; Stanford U. “I’m Kind of (Disappointed I Did Not Become) a Big Deal”: Status Disappointment, Future Work... Presenter: Eric Anicich; U. of Southern California Presenter: Merrick Osborne; USC Marshall School of Business Presenter: Andrea Villafuerte; USC Marshall School of Business

Senescent Progenitor Cells in the Skin of Patients with Cutaneous Lupus Erythematosus

Senescent Progenitor Cells in the Skin of Patients with Cutaneous Lupus Erythematosus

Ms2: A molecular simulation tool for thermodynamic properties, release 4.0

A new version release (4.0) of the molecular simulation tool ms2 (Deublein et al. 2011; Glass et al. 2014; Rutkai et al. 2017) is presented. Version 4.0 of ms2 features two additional potential functions to address the repulsive and dispersive interactions in a more versatile way, i.e. the Mie potential and the Tang–Toennies potential. This version further introduces Kirkwood–Buff integrals based on radial distribution functions, which allow the sampling of the thermodynamic factor of mixtures with up to four components, orientational distribution functions to elucidate mutual configurations of neighboring molecules, thermal diffusion coefficients of binary mixtures for heat, mass as well as coupled heat and mass transport, Einstein relations to sample transport properties with an alternative to the Green–Kubo formalism, dielectric constant of non-polarizable fluid models, vapor–liquid equilibria relying on the second virial coefficient and cluster criteria to identify nucleation. New version programm summaryProgram Title: ms2Program Files doi:http://dx.doi.org/10.17632/nsfj67wydx.3Licensing provisions: CC by NC 3.0Programming language: Fortran95Supplemental material: A detailed description of the parameter setup for the introduced methods, properties, functionalities etc. is given in the supplemental material. Furthermore, all molecular force field models developed by our group are provided by the MolMod Database: Stephan et al., Mol. Sim. 45 (2019) 806Journal reference of previous version: Deublein et al., Comput. Phys. Commun. 182 (2011) 2350 and Glass et al., Comput. Phys. Commun. 185 (2014) 3302 and Rutkai et al., Comput. Phys. Commun. 221 (2017) 343Does the new version supersede the previous version?: YesReasons for the new version: Introduction of new features as well as enhancement of computational efficiencySummary of revisions: Two new potential functions to address repulsive and dispersive interactions (Mie and Tang–Toennies potential), new properties (Helmholtz energy, Kirkwood–Buff integrals, thermodynamic factor, thermal diffusion coefficients, dielectric constant, mean squared displacement and non-Gaussian parameter), new functionalities (Kirkwood–Buff integration with extrapolation to the thermodynamic limit, van der Vegt correction for the radial distribution function, orientational distribution function, Einstein relations, vapor–liquid equilibria estimations, cluster criteria to identify nucleation).Nature of problem: Calculation of application-oriented thermodynamic properties: vapor–liquid equilibria of pure fluids and multi-component mixtures, thermal, caloric and entropic data as well as transport properties and data on microscopic structureSolution method: Molecular dynamics, Monte Carlo, various ensembles, Grand equilibrium method, Green–Kubo formalism, Einstein formalism, Lustig formalism, OPAS method, smooth-particle mesh Ewald summation.

The influence of binary mixtures' structuring on the calculation of Kirkwood-Buff integrals: A molecular dynamics study

The Kirkwood-Buff integrals (KBIs) provide a link between structuring on an atomic scale accessed by simulations and thermodynamics, which makes it a powerful tool for bridging the gap between microscopic and macroscopic quantities. Here we present the simulation study of the concentration dependence of KBIs for various types of binary ethanol mixtures which range from simple to complex. The thermodynamically ideal but extensively clustered methanol-ethanol mixture shows linearity in KBIs. The non-ideal mixtures, ethanol-water and ethanol-benzene, have the extrema in KBIs which are linked to the formation of the domains due to the association of molecules of the same species. We also explore some of the issues in KBI calculation, as KBI, a property of an open ensemble, is usually obtained by using the running integrals of a pair correlation function, calculated from the simulation of constant number of particles placed in a finite simulation box. The study includes a multifaceted analysis of the LP shift (J. Mol. Liq. 159, 52, 2011) and Ganguly and van der Vegt correction (J. Chem. Theory Comput. 9(3), 1347, 2013) of the radial distribution function, and compares different approaches in the computation of running KBI (J. Phys. Chem. Lett. 4(2), 235, 2013), both of which compensate for finite-size and ensemble effects. The results show how the best approach to the KBI calculation varies depending on the structural complexity of the simulated system.

Abstract CT018: Image guided surgery for tumor agnostic detection of solid tumors using the pH activated micellar imaging agent ONM-100: The Shine study

Abstract Introduction: ONM-100, an indocyanine green (ICG) conjugated, micelle-based polymer imaging agent with an exquisitely pH-sensitive binary activation mechanism, may be used for intra-operative tumor detection. Micelles dissociate in acidic environments resulting in fluorescent activation of ICG. As most solid cancer types are acidotic due to anaerobic glycolysis, the so-called Warburg effect, ONM-100 has the potential to act as a tumor agnostic imaging agent targeting a broad range of tumors. This first in-human study investigates the safety and feasibility of ONM-100 as a tumor agnostic imaging agent for intra-operative fluorescent imaging of various solid tumors. Methods: ONM-100 was IV administered 24±8h prior to surgery in a dose escalation scheme (0.1-1.2mg/kg), and the optimal dose was further evaluated in a subsequent cohort. Patients with histopathologically confirmed breast cancer (BC), head and neck squamous cell carcinoma (HNSCC), colorectal cancer (CRC) and esophageal cancer (EC) were included. Blood was drawn to assess safety and pharmacokinetic data. Intra-operative images were collected before and after tumor excision. After excision, fluorescence images were obtained from serially sliced specimens and formalin fixated paraffin embedded tissue blocks and correlated with standard histopathological assessment. Results: 30 patients (11 BC, 13 HNSCC, 3 EC, 3 CRC) were enrolled between March and December 2018. No ONM-100 related serious adverse events were observed and the agent was well tolerated at all the dose levels. A strong and sharply demarcated fluorescent signal was observed in all patients with vital tumor tissue (median Contrast to Noise Ratio 3.5; IQR 3.4) which correlated with tumor on final histopathology. Pharmacokinetics showed increased tumor fluorescence in a dose and plasma concentration-dependent manner. HNSCC, superficially located BC, extraluminal CRC as well as peritoneal metastasis could be clearly visualized in vivo during surgery. In 4 patients (BC and HNSCC), perioperatively, an otherwise unnoticed tumor by the surgeon was detected on the margin or wound bed using fluorescence imaging. Additionally, 2 BC tumor lesions were detected which were missed by conventional pre-operative imaging and pathological assessment. Conclusion: ONM-100 appears to be safe and allows fluorescent visualization of tumors both in- and ex vivo. The first in-human data demonstrates feasibility for potential use of ONM-100 for image guided surgery, detection of occult disease and margin assessment. Analysis of the microscopic biodistribution of ONM-100 is currently being performed and applications for metastatic lymph node detection will be explored. Note: This abstract was not presented at the meeting. Citation Format: Pieter J. Steinkamp, Floris J. Voskuil, Marjory Koller, Bert van der Vegt, Jan J. Doff, Tian Zhao, Jeffrey P. Hartung, Yalia Jayalakshmi, Baran D. Sumer, Jinming Gao, Max J. Witjes, Gooitzen M. van Dam. Image guided surgery for tumor agnostic detection of solid tumors using the pH activated micellar imaging agent ONM-100: The Shine study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT018.

Abstract P2-14-29: Image guided surgery for tumor detection in breast cancer using the PH activated micellar tracer ONM-100: The SHINE study

Abstract Background: Currently, no reliable intra-operative tumor detection and margin assessment technologies during breast conserving surgery are available. Fluorescence-guided surgery (FGS) using tumor specific fluorescent tracers can improve intra-operative tumor detection. However, a major limitation is the lack of broad tumor applicability due to complex oncogenotypes and histologic phenotypes. A strategy to overcome this challenge is targeting metabolic vulnerabilities that are more ubiquitous and regarded as generic hallmarks of cancer. The extracellular environment of tumors is relatively acidic compared to healthy tissue due to aerobic glycolysis, the so-called Warburg effect. ONM-100, a micellar polymer tracer labeled with the fluorescent imaging dye Indocyanine Green (ICG), has an exquisitely pH-sensitive binary on/off mechanism. The micelles dissociate in acidic environments causing the unquenching and fluorescent activation of the ICG dye. As most solid cancer types are acidotic, ONM-100 acts as a generic tracer targeting a broad range of tumors. This proof of concept, first in-human study, investigates the safety and feasibility of ONM-100 as an intra-operative fluorescent tracer in breast cancer (BC) patients. Methods: In this phase 1 study, the pH-activated fluorescent tracer ONM-100 was administered 24±8h prior to surgery in a dose escalation scheme ranging from 0.1 mg/kg to 0.8 mg/kg in groups of 3 patients each. Patients with biopsy proven BC were included. Patients that had undergone neoadjuvant therapy were excluded. Blood was drawn up to day 10 to assess safety and pharmacokinetic data. Intra-operative images were collected of the tumor before and after excision and of the wound bed. Immediately after excision ex vivo fluorescence images were obtained from the serially sliced specimen and the formalin fixated paraffin embedded tissue blocks. Fluorescence images were correlated with histopathological assessment on Hematoxylin and Eosin (H/E) stained sections. Results: In this ongoing clinical trial, 4 patients with BC were enrolled between March and May 2018. No tracer related (serious) adverse events were observed. A strong and sharply demarcated fluorescent signal in tumor tissue was observed in all 4 patients with in- and ex vivo imaging (median Contrast to Noise Ratio 6.5; IQR 7.25), which correlated with areas of tumor involvement on histopathology. In one BC patient, an intra-operatively unnoticed tumor positive margin was detected using fluorescence imaging. Additionally, a BC satellite lesion was detected, which was otherwise missed by the pathologist. Conclusion: Preliminary results of this ongoing first in-human study with the pH-activated tracer ONM-100 shows that ONM-100 is well tolerated and safe and allows fluorescent tumor visualization both in- and ex vivo. Here, we provide the first data that this pH-sensitive optical tracer can be used as a tracer for FGS and for margin detection. Further analysis on microscopic biodistribution of ONM-100 is currently being performed and possibilities for metastatic lymph node detection will be explored. Citation Format: Steinkamp PJ, Voskuil FJ, Koller M, van der Vegt B, Doff JJ, Zhao T, Hartung J, Jayalakshmi Y, Sumer BD, Gao J, Witjes MJ, van Dam GM. Image guided surgery for tumor detection in breast cancer using the PH activated micellar tracer ONM-100: The SHINE study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-14-29.

Abstract PD4-09: Non-invasive estrogen receptor assessment by [18F]-fluorestradiol(FES)-PET or circulating tumor cells predicts receptor status in patients with metastatic breast cancer

Abstract Introduction: Estrogen receptor (ER) expression largely determines the therapy choice for patients diagnosed with metastatic breast cancer (MBC). Given potential conversion of ER-status, the current golden standard for ER assessment is by immunohistochemistry (IHC) on metastatic tissue. Since a biopsy is cumbersome and sometimes not feasible, ER-status assessments by means of [18F]-fluorestradiol (FES)-PET or circulating tumor cells (CTCs) might be potential alternatives. We hypothesize that FES-PET or CTCs can determine ER status in patients with MBC, in a more efficient and patient friendly way than IHC. Methods: In the Dutch multicenter IMPACT-MBC trial (NCT01832051) patients with non-rapidly progressive MBC at first presentation, regardless of subtype, underwent extensive molecular imaging (including FES-PET, 89Zr-trastuzumab-PET and serial [18F]-fluorodeoxyglucose (FDG)-PET), a metastasis biopsy and blood sampling to obtain a whole body molecular profile of their disease. ER-status on the metastasis biopsy was evaluated by IHC and considered positive if ≥10% of the tumor cells showed ER expression. The FES-PET was considered positive when the maximum standardized uptake value (SUVmax) of at least one lesion was ≥ 1.5. Reverse transcription polymerase chain reaction was used to quantify the ESR1 expression in CTCs. ER-positivity was defined as an ESR1 mRNA ΔCq level ≥ -7.86, corrected for background healthy donor blood signal, only in samples with ≥5 CTCs/7.5ml and a sufficient mRNA signal of reference and epithelial genes. Sensitivity, specificity, positive and negative predictive values were calculated (PPV and NPV). Results: From 178 patients of 201 evaluable patients both metastasis IHC and FES-PET could be assessed. 129 of these 178 patients had an IHC ER positive metastasis (72%) and 133 patients had a positive FES-PET (75%). The PPV and NPV for IHC by FES-PET were 91% and 82%, respectively. From 54 of the 178 patients, blood samples contained sufficient CTCs for ESR1 analysis, allowing combined assessment of IHC, FES-PET and CTCs. ER positive CTCs were present in 45 patients (83%). Table 1 Metastasis ER positive (n=42)Metastasis ER negative (n=12)Sensitivity(%)PPV(%)Specificity(%)NPV(%)FES-PET positive4159889 CTC ER positive3879084 FES-PET and CTC positive3849090 FES-PET negative17 5888CTC ER negative45 4256FES-PET and CTC negative14 3380 Conclusion: In newly diagnosed patients with MBC, ER-status in metastatic lesions could be predicted by means of non-invasive FES-PET scan or CTCs. Prediction was most optimal with FES-PET compared to CTCs, and combining FES-PET with CTCs did not essentially improve this. Furthermore, CTCs were not detectable in most of these patients with non-rapidly progressive MBC, limiting their applicability for the present purpose. However, as CTC assessment is most patient friendly, CTCs might be considered as first step in determining MBC ER-status. If ER positive CTCs are detected, ER positive disease is very likely; if no- or ER negative CTCs are detected, MBC ER-status needs to be further assessed by means of tissue confirmation or FES-PET. Funding: Dutch Cancer Society grant RUG 2012-5565, project EMCR 16-8196 Citation Format: Eisses B, Angus L, van der Vegt B, Sieuwerts AM, Kraan J, Martens JW, Glaudemans AW, Brouwers AH, Hoekstra OS, Oyen W, Emmering J, Gerritse S, Menke-van der Houven van Oordt CW, Boon E, van Herpen CM, Jager A, Sleijfer S, de Vries EG, Schröder CP. Non-invasive estrogen receptor assessment by [18F]-fluorestradiol(FES)-PET or circulating tumor cells predicts receptor status in patients with metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD4-09.

Abstract P4-02-01: Analytical validation of an automated digital scoring protocol for Ki67: International multicenter collaboration study

Abstract Background/Goal: Ki67 expression has been a valuable prognostic marker in breast cancer, but has not seen broad adoption due to lack of standardization between institutions. Automation could represent a solution. Here we tested 3 automated digital image analysis (DIA) platforms including an open source platform to: (i) Investigate the reproducibility of Ki67 measurement across platforms with supervised classifiers performed by the same operator and by multiple operators. (ii) Compare accuracy of the 3 DIA platforms against outcome (prognostic potential). (iii) Assess inter-laboratory reproducibility of a calibrated DIA tool to evaluate Ki67 in breast cancer among 10 participating labs of the International Ki67 in Breast Cancer Working Group (IKWG). Methods: The Mib-1 antibody (Dako) was used to detect Ki67 (dilution 1:100). HALO (H) (IndicaLabs), QuantCenter (QC) (3DHistech), QuPath (QP) (open-source software) digital image analysis (DIA) platforms were used to evaluate Ki67 expression. As a ground truth, we evaluated Ki67 LI with meticulous manual tissue segmentation using the Spectrum Webscope (SW) (Aperio). Calibration was performed using 30 ER+ breast cancer cases from phase 3 of the IKWG initiative where blocks were centrally cut and stained for Ki67. The inter-laboratory analysis was done with 10 participating laboratories divided into 2 groups where members within the same group were given the same set of images. The outcome cohort consisted of 149 breast cancer cases from the Yale Pathology archives in tissue microarray format. Intra-class correlation coefficient (ICC) was used to measure reproducibility with the pre-specified criterion for success being to exceed 0.80. Kaplan-Meier analysis supported with log-rank test was performed to assess prognostic potential. Results: All 3 DIA platforms showed excellent inter-platform reproducibility (ICC: 0.933, CI: 0.879-0.966). Also, excellent reproducibility was found between all DIA platforms and the reference standard Ki67 values of SW (QP ICC: 0.970, CI: 0.936-0.986; H ICC: 0.968, CI: 0.933-0.985; QC ICC: 0.964, CI: 0.919-0.983). The intra-DIA reproducibility was also excellent for all platforms (QP ICC: 0.992, CI: 0.986-0.996; H ICC: 0.972, CI: 0.924-0.988; QC ICC: 0.978, CI: 0.932-0.991). Comparing each DIA against outcome, the hazard ratios were similar (QP=3.309, H=3.077, QC=3.731). The inter-operator reproducibility was particularly high (ICC: 0.962-0.995). As QP is open source software and also showed the lowest intra-DIA platform variability, we selected the QP platform to investigate inter-laboratory reproducibility among 10 IKWG labs. The different-section ICC across the 10 labs was 0.974 (CI: 0.954 - 0.986). The same-section ICC estimate was 0.984 (CI: 0.971-0.992) for group 1 and 0.978 (CI: 0.956-0.989) for group 2. Conclusions: Our results showed outstanding reproducibility both within and between DIA platforms. We also found the platforms essentially indistinguishable with respect to prediction of breast cancer patient outcome. Automated Ki67 evaluation using a calibrated, open-source DIA platform (QuPath) met the pre-specified criterion of success in the multi-institutional setting. Assessment of clinical utility is planned. Citation Format: Acs B, Leung SC, Pelekanou V, Bai Y, Martinez-Morilla S, Toki M, Chang MC, Gholap A, Jadhav A, Hugh JC, Bigras G, Laurinavicius A, Augulis R, Levenson R, Todd A, Piper T, Virk S, van der Vegt B, Hayes DF, Dowsett M, Nielsen TO, Rimm DL. Analytical validation of an automated digital scoring protocol for Ki67: International multicenter collaboration study [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-02-01.