Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia.

Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956.

Coal Is Not Black, Snow Is Not White, Food Is Not a Reinforcer: The Roles of Affordances and Dispositions in the Analysis of Behavior.

Reinforcers comprise sequences of actions in context. Just as the white of snow and black of coal depend on the interaction of an organism's visual system and the reflectances in its surrounds, reinforcers depend on an organism's motivational state and the affordances-possibilities for perception and action-in its surrounds. Reinforcers are not intrinsic to things but are a relation between what the thing affords, its context, the organism, and his or her history as capitulated in their current state. Reinforcers and other affordances are potentialities rather than intrinsic features. Realizing those potentialities requires motivational operations and stimulus contexts that change the state of the organism-they change its disposition to make the desired response. An expansion of the three-term contingency is suggested in order to help keep us mindful of the importance of behavioral systems, states, emotions, and dispositions in our research programs.

Polarization imaging and classification of Jurkat T and Ramos B cells using a flow cytometer.

Label-free and rapid classification of cells can have awide range of applications in biology. We report a robust method of polarization diffraction imaging flow cytometry (p-DIFC) for achieving this goal. Coherently scattered light signals are acquired from single cells excited by a polarized laser beam in the form of two cross-polarized diffraction images. Image texture and intensity parameters are extracted with a gray level co-occurrence matrix (GLCM) algorithm to obtain an optimized set of feature parameters as the morphological "fingerprints" for automated cell classification. We selected the Jurkat T cells and Ramos B cells to test the p-DIFC method's capacity for cell classification. After detailed statistical analysis, we found that the optimized feature vectors yield accuracies of classification between the Jurkat and Ramos ranging from 97.8% to 100% among different cell data sets. Confocal imaging and three-dimensional reconstruction were applied to gain insights on the ability of p-DIFC method for classifying the two cell lines of highly similar morphology. Based on these results we conclude that the p-DIFC method has the capacity to discriminate cells of high similarity in their morphology with "fingerprints" features extracted from the diffraction images, which may be attributed to subtle but statistically significant differences in the nucleus-to-cell volume ratio in the case of Jurkat and Ramos cells.

Analysis of diffraction imaging in non-conjugate configurations.

Diffraction imaging of scattered light allows extraction of information on scatterer's morphology. We present a method for accurate simulation of diffraction imaging of single particles by combining rigorous light scattering model with ray-tracing software. The new method has been validated by comparison to measured images of single microspheres. Dependence of fringe patterns on translation of an objective based imager to off-focus positions has been analyzed to clearly understand diffraction imaging with multiple optical elements. The calculated and measured results establish unambiguously that diffraction imaging should be pursued in non-conjugate configurations to ensure accurate sampling of coherent light distribution from the scatterer.

The effects of response disequilibrium on social media use: A laboratory analogue.

Response disequilibrium is the perturbation of unconstrained behavior with a contingency. For example, the imposition of advertisements before or after viewing TikTok videos. The purpose of this laboratory analogue was to determine the effects of two such response disequilibrium conditions: (1) which required participants to view 5 s increments of advertisements to access 2 s increments of TikTok videos and (2) which required participants to view 5 s increments of TikTok videos to access 15 s increments of advertisements. The disequilibrium condition in (1) is called a response deficit due to the restricted access to TikTok videos relative to baseline while (2) is called a response excess due to the overabundance of advertisements relative to baseline. Additionally, participants had access to a third activity that was freely available throughout. Participants could browse images of TikTok video thumbnails while in deficit and excess. As predicted, participants increased their viewing of advertisements when TikTok was in deficit and decreased their viewing of TikTok when advertisements were in excess. Furthermore, some participants substituted TikTok with browsing during the excess of advertisements. This investigation has implications for a behavioral economic analysis of social media use and the contingency management of time spent on these platforms.

Study of low speed flow cytometry for diffraction imaging with different chamber and nozzle designs.

Achieving effective hydrodynamic focusing and flow stability at low speed presents a challenging design task in flow cytometry for studying phenomena such as cell adhesion and diffraction imaging of cells with low-cost cameras. We have developed different designs of flow chamber and sheath nozzle to accomplish the above goal. A 3D computational model of the chambers has been established to simulate the fluid dynamics in different chamber designs and measurements have been performed to determine the velocity and size distributions of the core fluid from the nozzle. Comparison of the simulation data with experimental results shows good agreement. With the computational model significant insights were gained for optimization of the chamber design and improvement of the cell positioning accuracy for study of slow moving cells. The benefit of low flow speed has been demonstrated also by reduced blurring in the diffraction images of single cells. Based on these results, we concluded that the new designs of chamber and sheath nozzle produce stable hydrodynamic focusing of the core fluid at low speed and allow detailed study of cellular morphology under various rheological conditions using the diffraction imaging method.

The Effects of Obligatory and Preferential Frames on Delay Discounting.

Human decision making is partly determined by the verbal stimuli involved in a choice. Verbal stimuli that may be particularly relevant to human decision making are the words should and like, whereby should is presumably associated with what one ought to choose, and like is presumably associated with what one prefers to choose. The current study examined the potential effects of should and like on decisions in a monetary delay-discounting task. Eighty-three participants were recruited from Amazon's Mechanical Turk and were randomly assigned to a sequence of 2 conditions-should and like-in a repeated-measures experimental design. Based on condition assignment, the questions "Which should you choose?" and "Which would you like to choose?" appeared above each monetary option and its respective delay. Overall, participants demonstrated significantly lower levels of discounting in the should condition when compared to the like condition. However, this effect was much less consistent for participants exposed to the should condition prior to the like condition. The results of the current investigation indicate that the use of the words should and like constitutes separate classes of verbal stimuli that we refer to as obligatory and preferential frames. The effect of obligatory and preferential frames on delay discounting may be relevant to the prediction and control of decision making in social contexts.

Development of a diffraction imaging flow cytometer.

Diffraction images record angle-resolved distribution of scattered light from a particle excited by coherent light and can correlate highly with the 3D morphology of a particle. We present a jet-in-fluid design of flow chamber for acquisition of clear diffraction images in a laminar flow. Diffraction images of polystyrene spheres of different diameters were acquired and found to correlate highly with the calculated ones based on the Mie theory. Fast Fourier transform analysis indicated that the measured images can be used to extract sphere diameter values. These results demonstrate the significant potentials of high-throughput diffraction imaging flow cytometry for extracting 3D morphological features of cells.

Replicability and randomization test logic in behavior analysis.

Randomization tests are a class of nonparametric statistics that determine the significance of treatment effects. Unlike parametric statistics, randomization tests do not assume a random sample, or make any of the distributional assumptions that often preclude statistical inferences about single-case data. A feature that randomization tests share with parametric statistics, however, is the derivation of a p-value. P-values are notoriously misinterpreted and are partly responsible for the putative "replication crisis." Behavior analysts might question the utility of adding such a controversial index of statistical significance to their methods, so it is the aim of this paper to describe the randomization test logic and its potentially beneficial consequences. In doing so, this paper will: (1) address the replication crisis as a behavior analyst views it, (2) differentiate the problematic p-values of parametric statistics from the, arguably, more useful p-values of randomization tests, and (3) review the logic of randomization tests and their unique fit within the behavior analytic tradition of studying behavioral processes that cut across species.

An Empirical Evaluation of the Disequilibrium Model to Increase Independent Seatwork for an Individual Diagnosed with Autism.

This brief practice is an evaluation of work output predicted by Timberlake's (1980) disequilibrium model. Jacobs, Morford, King, and Hayes (2017) provided a downloadable, online tool using the disequilibrium model to assist practitioners in maximizing intervention outcomes. The disequilibrium model was used to predict the duration of independent seatwork for Marvin, a 17-year-old boy diagnosed with autism spectrum disorder. The disequilibrium model effectively predicted a work duration that Marvin was compliant with throughout the study. Practitioners should consider using the disequilibrium tool to select intervention parameters.

Disequilibrium in behavior analysis: A disequilibrium theory redux.

Disequilibrium theory is an approach to reinforcement that reconsiders the putative response strengthening prowess of stimuli. This disequilibrium approach-the pinnacle of the response deprivation hypothesis-reliably predicts changes in behavior without reference to a response strengthening process. While the strengthening model of reinforcement has received renewed and critical appraisal in behavior analysis, its appraisers have not fully considered the role that a disequilibrium conceptualization might play in their respective theories of reinforcement. In this essay we celebrate William Timberlake's legacy by elucidating the assumptions of disequilibrium theory and by exploring its predictions and implications within behavior analysis. We treat the disequilibrium approach to reinforcement as the theory of reinforcement in behavior analysis, and in doing so, we distinguish disequilibrium conditions from motivating operations and explore future directions regarding the potential to predict generalization and maintenance outcomes. The disequilibrium approach to reinforcement is not a mere deprivation operation used for the purposes of establishing a stimulus as a "reinforcer," as it is a general theory of behavior.

Angle-resolved Mueller matrix study of light scattering by B-cells at three wavelengths of 442, 633, and 850 nm.

Angle-resolved signals of polarized light scattered by biological cells provide rich information on cell morphology. Quantitative study of these signals can lead to new methods to develop and improve high-throughput instrumentation for cell probing such as scattering-based flow cytometry. We employ a goniometer system with a photoelastic modulation scheme to determine selected Mueller matrix elements of B-cell hydrosol samples. The angular dependence of S(11), S(12), and S(34) is determined from the scattered light signals between 10 and 160 deg at the three wavelengths 442, 633, and 850 nm. A finite-difference, time-domain (FDTD) method and coated-sphere model are used to investigate the effect of nuclear refractive index on the angle-resolved Mueller elements at different wavelengths using the 3-D structures of selected B cells reconstructed from confocal images. With these results, we demonstrate the value of the light-scattering method in obtaining the cell morphology information.

Predicting the Effects of Interventions: A Tutorial on the Disequilibrium Model.

The disequilibrium approach to reinforcement and punishment, derived from the probability-differential hypothesis and response deprivation hypothesis, provides a number of potentially useful mathematical models for practitioners. The disequilibrium approach and its accompanying models have proven effective in the prediction and control of behavior, yet they have not been fully espoused and integrated into clinical practice. The purpose of this tutorial is to detail the disequilibrium approach and adapt its mathematical models for use as a tool in applied settings. The disequilibrium models specify how to arrange contingencies and predict the effects of those contingencies. We aggregate these models, and provide them as a single tool, in the form of a Microsoft Excel® spreadsheet that calculates the direction and magnitude of behavior change based on baseline measures and a practitioner's choice of intervention parameters. How practitioners take baseline measures and select intervention parameters in accordance with disequilibrium models is explicated. The proposed tool can be accessed and downloaded for use at https://osf.io/knf7x/.

Noninvasive Quantification of Blood Flow in Epicardial Coronary Arteries, Coronary Artery Bypass Grafts, and Anastomoses.

OBJECTIVE: Direct flow measurement in native epicardial coronary arteries, bypass conduits, and anastomoses is severely limited by the invasiveness and inaccuracy of existing technologies. As a result, less than 25% of patients undergoing coronary artery bypass grafting (CABG) worldwide have any intraoperative evaluation performed. A simple, accurate, and noninvasive technology to directly quantify blood flow and rheology surrounding anastomotic sites is a critical unmet need in CABG. METHODS: Existing technology limitations drove development of a different technology solution. With an optical physics approach, flow in conduits and tissue can be quantified in real time with nonionizing broad-spectrum imaging as well as temporal and spatial analyses. Cardiac motion, calibration, and combining anatomy + physiology in imaging were challenges requiring solutions. RESULTS: This patented imaging technology was developed and tested in an established porcine cardiac experimental model and in clinical proof-of-concept studies. Flow velocities and flows in epicardial coronary arteries vary physiologically with the cardiac cycle and with acute ischemia, as predicted by previous studies using traditional technologies. Imaging data are captured from a 30-cm viewing distance, analyzed and displayed in real time as a video. The field of view enables capture of flow in the proximal and distal epicardial coronary, the conduit, at the anastomosis and in the distal myocardium simultaneously. CONCLUSIONS: Rheologic flow interaction between conduit and native coronary at the anastomosis remains the most poorly understood technical aspect of CABG. A noninvasive, noncontact, no-risk imaging technology as simple as a snapshot can provide this critical physiologic information, validate and document intraoperative quality, and improve even further CABG outcomes.

A primary method for determination of optical parameters of turbid samples and application to intralipid between 550 and 1630 nm.

The lack of a primary method for determination of optical parameters remains a significant barrier in optical study of turbid media. We present a complete system of experimental setups and Monte Carlo modeling tools for fast and accurate solution of the inverse problem from the measured signals of homogeneous turbid samples. The calibration of the instrument and validation of the Monte Carlo modeling have been carried out to ensure the accuracy of the inverse solution. We applied this method to determine the optical parameters of turbid media of 10% intralipid between 550 and 940 nm and 20% intralipid between 550 and 1630 nm.

Local delivery of granulocyte macrophage colony-stimulating factor by retrovirally transduced antigen-specific T cells leads to severe, chronic experimental autoimmune encephalomyelitis in mice.

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease of the central nervous system (CNS) that can be induced in susceptible mice by the transfer of autoreactive T cells that recognize myelin basic protein (MBP). The onset and subsequent recovery from disease are associated with distinct patterns of cytokine and chemokine expression within the inflammatory lesions of the CNS. Given the likely importance of the local cytokine milieu in regulating the disease process, it would be preferable to administer cytokines locally to the CNS and reduce systemic delivery in order to evaluate their immunoregulatory roles in EAE. For this purpose, we have used retrovirally transduced T cells from MBP-specific T cell receptor transgenic mice in an attempt to target cytokine delivery to the CNS where MBP is primarily expressed. We have found that T cells expressing granulocyte macrophage colony-stimulating factor (GM-CSF) induce severe, chronic EAE from which mice fail to recover. Our results indicate that increased local GM-CSF expression could play an important role in inducing chronic EAE.

Temporal associations between interleukin 22 and the extracellular domains of IL-22R and IL-10R2.

Interleukin 22 (IL-22) is a cytokine induced during both innate and adaptive immune responses. It can effect an acute phase response, implicating a role for IL-22 in mechanisms of inflammation. IL-22 requires the presence of the IL-22 receptor (IL-22R) and IL-10 receptor 2 (IL-10R2) chains, two members of the class II cytokine receptor family (CRF2), to effect signal transduction within a cell. We studied the interaction between human IL-22 and the extracellular domains (ECD) of its receptor chains in an enzyme-linked immunoabsorbant assay (ELISA)-based format, using biotinylated IL-22 (bio-IL-22) and receptor-fusions containing the ECD of a receptor fused to the Fc of hIgG1 (IL-22R-Fc and IL-10R2-Fc). IL-22 has measurable affinity for IL-22R-Fc homodimer and undetectable affinity for IL-10R2. IL-22 has substantially greater affinity for IL-22R/IL-10R2-Fc heterodimers. Further analyses involving sequential additions of receptor homodimers and cytokine indicates that the IL-10R2(ECD) binds to a surface created by the interaction between IL-22 and the IL-22R(ECD), and thereby further stabilizes the association of IL-22 within this cytokine-receptor-Fc complex. Both a neutralizing rat monoclonal antibody, specific for human IL-22, and human IL-22BP-Fc, an Fc-fusion of the secreted IL-22 binding-protein and proposed natural antagonist for IL-22, bind to similar cytokine epitopes that may overlap the binding site for IL-22R(ECD). Another rat monoclonal antibody, specific for IL-22, binds to an epitope that may overlap a separate binding site for IL-10R2(ECD). We propose, based on this data, a temporal model for the development of a functional IL-22 cytokine-receptor complex.

Determination of complex refractive index of polystyrene microspheres from 370 to 1610 nm.

We introduce an inverse method for determining simultaneously the real and imaginary refractive indices of microspheres based on integrating sphere measurements of diffuse reflectance and transmittance, and Monte Carlo modelling in conjunction with the Mie theory. The results for polystyrene microspheres suspended in water are presented.