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Aim Left ventricular (LV) lead position at the latest mechanically activated non-scarred myocardial LV region confers improved response to cardiac resynchronization therapy (CRT). We conducted a double-blind, randomized controlled trial to evaluate the clinical benefit of multimodality imaging-guided LV lead placement in CRT. Methods and results Patients were allocated (1:1) to imaging-guided LV lead placement using cardiac computed tomography (CT) venography, 99mTechnetium myocardial perfusion imaging, and speckle-tracking echocardiography radial strain to target the optimal coronary sinus (CS) branch closest to the non-scarred myocardial segment with latest mechanical activation (imaging group, n = 89) or to routine LV lead implantation in a posterolateral region with late electrical activation (control group, n = 93). The primary endpoint was clinical non-response to CRT [≥1 of the following after 6 months: (1) death, (2) heart failure hospitalization, or (3) no improvement in New York Heart Association class and

A noninvasive in vivo imaging method for NK cell trafficking is essential to gain further understanding of the pathogenesis of NK cell mediated immune response to the novel cancer treatment strategies, and to discover the homing sites and physiological distribution of NK cells. Although human NK tells can be labeled for in vivo imaging, little is known about the murine NK cell labeling and its application in animal models. This study describes the isolation and ex vivo radiolabeling of murine NK cells for the evaluation of cell trafficking in an orthotopic model of human lung cancer in mice. Scid-Tg(FCGR3A)Blt transgenic SCID mice were used to isolate NK tells from mouse splenotytes using the CD49b (DXS) MicroBeads positive selection method. The purity and viability of the isolated NK cells were confirmed by FACS analysis. Different labeling buffers and incubation times were evaluated to optimize In-111-oxine labeling conditions. Functionality of the radiolabeled NK cell was assessed by Cr-51-release assay. We evaluated physiological distribution of In-111-oxine labeled murine NK cells in normal SCID mice, and biodistribution in irradiated and nonirradiated SCID mice with orthotopic A549 human lung tumor lesions. Imaging findings were confirmed by histology. Results showed that incubation with 0.011 MBq of In-111-oxine per million murine NK cells in PBS (pH 7.4) for 20 min is the best condition that provides optimum labeling efficiency without affecting cell viability and functionality. Physiological distribution in normal SCID mice demonstrated NK cells homing mainly in the spleen, while In-111 released from NK cells was excreted via kidneys into urine. Biodistribution studies demonstrated a higher lung uptake in orthotopic lung tumor-bearing mice than control mice. In irradiated mice, lung tumor uptake of radiolabeled murine NK cells decreased between 24 h and 72 h postinjection (p.i.), which was accompanied by tumor regression, while in nonirradiated mice, radiolabeled NK cells were retained in the lung tumor lesions up to 72 h p.i. without tumor regression. In tumor-bearing mice that were only irradiated but did not receive radiolabeled murine NK cells, a high tumor burden was observed at 72 h p.i., which indicates that irradiation in combination with murine NK cell allocation, but not irradiation alone, induced a remarkable antitumor effect in the orthotopic A549 lung tumor bearing mouse model. In conclusion, we describe a method to evaluate murine NK cell trafficking and biodistribtition, which can be used to determine potential effects of immune mediated therapeutic agents on NK cell biodistribution.

Steer-by-wire technology enables vehicle safety systems to share control with a driver through augmentation of the driver's steering commands. Advances in sensing technologies empower these systems further with real-time information about the surrounding environment. Leveraging these advancements in vehicle actuation and sensing, the authors present a shared control framework for obstacle avoidance and stability control using two safe driving envelopes. One of these envelopes is defined by the vehicle handling limits, whereas the other is defined by spatial limitations imposed by lane boundaries and obstacles. A model predictive control (MPC) scheme determines at each time step if the current driver command allows for a safe vehicle trajectory within these two envelopes, intervening only when such a trajectory does not exist. In this way, the controller shares control with the driver in a minimally invasive manner while avoiding obstacles and preventing loss of control. The optimal control problem underlying the controller is inherently nonconvex but is solved as a set of convex problems allowing for reliable real-time implementation. This approach is validated on an experimental vehicle working with human drivers to negotiate obstacles in a low friction environment.

New sensing and steering technologies enable safety systems that work with the driver to ensure a safe and collision-free vehicle trajectory using a shared control approach. These shared control systems must constantly balance the sometimes competing objectives of following the driver’s command and maintaining a feasible trajectory for the vehicle. This paper presents a novel technique for creating haptic steering feedback based on a prediction of the system’s need to intervene in the future. This feedback mirrors the tension between the two controller objectives of following the driver and maintaining a feasible path. The paper uses simulation and experiment to investigate the impact of varying the prediction horizon on system performance. A novel in-vehicle driver study based on decoupling visual and haptic cues demonstrates that this feedback provides a statistically significant improvement in response time and reduced time to collision (TTC) in an obstacle avoidance task.

BACKGROUND: Remote monitoring (RM) is an established technology integrated into routine follow-up of patients with implantable cardioverter-defibrillator (ICD). Current RM systems differ according to transmission frequency and alert definition.OBJECTIVE: We aimed to compare time difference between detection and acknowledgement of clinically relevant events between four RM systems.METHODS: We analyzed time delay between detection of ventricular arrhythmic and technical events by the ICD and acknowledgement by hospital staff in 1.802 consecutive patients followed with RM during September 2014 - August 2016. Devices from Biotronik (BIO, n=374), Boston Scientific (BSC, n=196), Medtronic (MDT, n=468) and St Jude Medical (SJM, n=764) were included. We identified all events from RM webpages and their acknowledgement with RM or at in-clinic follow-up. Events occurring during weekends were excluded.RESULTS: We included 3.472 events. Proportion of events acknowledged within 24 hours was 72%, 23%, 18% and 65% with BIO, BSC, MDT and SJM, respectively, with median times of 13, 222, 163 and 18 hours from detection to acknowledgement (pCONCLUSION: Significant and clinically relevant differences in time delay from event detection to acknowledgement exist between RM systems. Varying definitions of which events RM transmits as alerts are important for the differences observed.

Aims: In a randomized trial of cardiac resynchronization therapy (CRT), a presumed optimal left ventricular (LV) lead position close to the latest mechanically activated non-scarred myocardium was achieved in 98% of patients by standard implantation. We evaluated whether inter-lead electrical delay (IED) was associated with response to CRT in these patients.Methods and results: We prospectively included 160 consecutive patients undergoing CRT. Pre-implant speckle-tracking echocardiography radial strain and 99mTc myocardial perfusion imaging determined the latest mechanically activated non-scarred myocardial segment. We measured procedural IED as the time interval between sensed signals in right ventricular and LV lead electrograms. All patients had LV pacing site concordant or adjacent to the latest mechanically activated non-scarred segment verified by cardiac computed tomography. Response to CRT was defined as ≥15% reduction in LV end-systolic volume at 6 months follow-up. Selecting a practical IED cut-off value of 100 ms, more patients with long IED than patients with short IED responded to CRT (87 vs. 68%; P = 0.004). In multivariate logistic regression analysis, IED ≥100 ms remained associated with CRT response after adjusting for baseline characteristics, including QRS duration and scar burden [odds ratio 3.19 (1.24-8.17); P = 0.01]. Categorizing IED by tertiles, CRT response improved with longer IED (P = 0.03). Comparable response rates were observed in patients with a concordant and adjacent LV lead position.Conclusion: A longer IED was associated with more pronounced LV reverse remodelling response in CRT recipients with a presumed optimal LV lead position concordant or adjacent to the latest mechanically activated non-scarred segment.

Human drivers navigate the roadways by balancing values such as safety, legality, and mobility. The public will likely judge an autonomous vehicle by similar values. The iterative methodology of value sensitive design formalizes the connection of human values to engineering specifications. We apply a modified value sensitive design methodology to the development of an autonomous vehicle speed control algorithm to safely navigate an occluded pedestrian crosswalk. The first iteration presented here models the problem as a partially observable Markov decision process and uses dynamic programming to compute an optimal policy to control the longitudinal acceleration of the vehicle based on the belief of a pedestrian crossing. The speed control algorithm is then tested in real-time on an experimental vehicle on a closed road course.

This paper presents a feedback-feedforward steering controller that simultaneously maintains vehicle stability at the limits of handling while minimising lateral path tracking deviation. The design begins by considering the performance of a baseline controller with a lookahead feedback scheme and a feedforward algorithm based on a nonlinear vehicle handling diagram. While this initial design exhibits desirable stability properties at the limits of handling, the steady-state path deviation increases significantly at highway speeds. Results from both linear and nonlinear analyses indicate that lateral path tracking deviations are minimised when vehicle sideslip is held tangent to the desired path at all times. Analytical results show that directly incorporating this sideslip tangency condition into the steering feedback dramatically improves lateral path tracking, but at the expense of poor closed-loop stability margins. However, incorporating the desired sideslip behaviour into the feedforward loop creates...

Drivers use torque feedback at the handwheel of a vehicle, or steering feel, to obtain information about the road and tire dynamics. This aids them in driving tasks like curve negotiation. Steer-by-wire vehicles, due to the mechanical decoupling of the front tires and handwheel, do not have any inherent steering feedback and require an artificial steering feel. One way to implement an artificial steering feel is to synthesize steering feedback with a model running on board the vehicle. Identifying the appropriate level of model fidelity required involves understanding what elements of steering feel are important. This paper proposes using objective steering feel measures used in industry as a means of understanding which elements of steering feel are most important. It also introduces a steering feel model of appropriate fidelity to capture these important elements of steering feel while remaining intuitive to tune objectively with a small set of parameters. Experimental data show that the desired performance measures obtained via dynamic vehicle simulation can be replicated on an actual steer-by-wire vehicle, validating the design technique.

The present case report presents two cases in which automatic threshold measurement features in an implantable cardiac defibrillator and in a CRTD act proarrhythmic by inducing polymorphic ventricular arrhythmia. By programming these features off the problem was solved. The mechanisms seem to be different from previously reported proarrhythmic interactions from such device features.

Visuomotor ability is quite crucial for everyday functioning, particularly in driving and sports. While there is accumulating evidence regarding neural correlates of visuomotor transformation, less is known about the brain regions that accommodate visuomotor mapping under different cognitive demands. We concurrently measured cortical activity and pupillary response, using functional near infrared spectroscopy (fNIRS) and eye-tracking glasses, to examine the neural systems linked to pupil dilation under varying cognitive demands. Twenty-three healthy adults performed two sessions of a navigation task, in which the cognitive load was manipulated by either reversing the visuomotor mapping or increasing the speed of the moving object. We identified a region in the right superior parietal lobule that responded to both types of visuomotor load and its activity was associated with larger pupillary response and better performance in the task. Our multimodal analyses suggest that activity in this region arises from the need for increased attentional effort and alertness for visuomotor control and is an ideal candidate for objective measurement of visuomotor cognitive load. Our data extend previous findings connecting changes in pupil diameter to neural activity under varying cognitive demand and have important implications for examining brain-behavior associations in real-world tasks such as driving and sports.

The ability to use all of the available tire force is essential to road vehicles for emergency maneuvers and racing. As the front tires of an understeering vehicle saturate while cornering at the limit of tire-road friction, steering is lost as a control input for path-tracking. Experimental data from an autonomous vehicle show that for path-tracking at the limit of friction through steering the value of friction needs to be known to within approximately 2%. This requirement exceeds the capabilities of existing real-time friction estimation algorithms. Data collected with a professional race car driver inspire a novel control framework, with a slip angle-based control strategy of maintaining the front tires at the slip angle for which maximum tire force is attained, and longitudinal speed control for path-tracking. This approach has significantly less demanding requirements on the accuracy of friction estimation. A controller is presented to explore this concept, and experimental results demonstrate successful tracking of a circular path at the friction limit without a priori friction information.

A new method is presented for low-level steering control of autonomous vehicles. By tracking tire slip angle instead of steering angle, the new controller makes possible a more direct use of force-based high-level control schemes since uncertain, noisy measurements of the vehicle states do not have to be used to convert a desired tire slip angle to a commanded steer angle. Experimental data from a full-size vehicle show that this approach offers some advantages when combined with a force-based path tracking controller. Improved steering control and path tracking performance are demonstrated, particularly at the limits of tire friction, and the reasons for these improvements are briefly discussed.

We developed cergutuzumab amunaleukin (CEA-IL2v, RG7813), a novel monomeric CEA-targeted immunocytokine, that comprises a single IL-2 variant (IL2v) moiety with abolished CD25 binding, fused to the C-terminus of a high affinity, bivalent carcinoembryonic antigen (CEA)-specific antibody devoid of Fc-mediated effector functions. Its molecular design aims to (i) avoid preferential activation of regulatory T-cells vs. immune effector cells by removing CD25 binding; (ii) increase the therapeutic index of IL-2 therapy by (a) preferential retention at the tumor by having a lower dissociation rate from CEA-expressing cancer cells vs. IL-2R-expressing cells, (b) avoiding any FcγR-binding and Fc effector functions and (c) reduced binding to endothelial cells expressing CD25; and (iii) improve the pharmacokinetics, and thus convenience of administration, of IL-2. The crystal structure of the IL2v-IL-2Rβγ complex was determined and CEA-IL2v activity was assessed using human immune effector cells. Tumor targeting was investigated in tumor-bearing mice using 89Zr-labeled CEA-IL2v. Efficacy studies were performed in (a) syngeneic mouse models as monotherapy and combined with anti-PD-L1, and in (b) xenograft mouse models in combination with ADCC-mediating antibodies. CEA-IL2v binds to CEA with pM avidity but not to CD25, and consequently did not preferentially activate Tregs. In vivo, CEA-IL2v demonstrated superior pharmacokinetics and tumor targeting compared with a wild-type IL-2-based CEA immunocytokine (CEA-IL2wt). CEA-IL2v strongly expanded NK and CD8+ T cells, skewing the CD8+:CD4+ ratio toward CD8+ T cells both in the periphery and in the tumor, and mediated single agent efficacy in syngeneic MC38-CEA and PancO2-CEA models. Combination with trastuzumab, cetuximab and imgatuzumab, all of human IgG1 isotype, resulted in superior efficacy compared with the monotherapies alone. Combined with anti-PD-L1, CEA-IL2v mediated superior efficacy over the respective monotherapies, and over the combination with an untargeted control immunocytokine. These preclinical data support the ongoing clinical investigation of the cergutuzumab amunaleukin immunocytokine with abolished CD25 binding for the treatment of CEA-positive solid tumors in combination with PD-L1 checkpoint blockade and ADCC competent antibodies.

For over a decade, mechanical creatures have formed the basis for the final project in a large engineering class on mechanical systems design. Each year a different real or fictitious animal provides the inspiration and design requirements for synthesizing, fabricating, and analyzing mechanisms and power transmission systems to achieve a plausible biomimetic motion. We explore why biomimetic creatures are particularly suited to learning about mechanisms, and discuss implementation details and pedagogical insights based on our experience.

Late-phasing homogeneous charge compression ignition operating conditions have the potential to expand the useful operating range of homogeneous charge compression ignition in internal combustion engines. However, significant combustion instabilities can occur at late-phasing operating conditions. Combustion phasing and work output variations at these conditions are characterized by a pattern in which the combustion phasing alternates between being earlier than the desired timing and later than the desired timing. This characteristic can be traced to a negative eigenvalue in a simplified, discrete-time analytical model of homogeneous charge compression ignition dynamics. The model forms the basis for the design of a simple controller that is shown to reduce combustion timing variations in simulation. Experimental results illustrate the controller successfully reduces the cyclic variations in combustion by altering the exhaust valve timing, resulting in stable combustion and an expanded operating range.

AIMS: To assess the long-term mortality and occurrence of post-ablation atrial fibrillation in patients undergoing a radiofrequency ablation for the Wolff-Parkinson-White (WPW) syndrome.METHODS AND RESULTS: A retrospective cohort study of patients (N = 362) subjected to radiofrequency ablation of the WPW syndrome at Aarhus University Hospital from 1990 to 2011. A comparison cohort (N = 3619) was generated from the Danish National Board of Health Central Population Registry. We found no significant difference in all-cause mortality when comparing the WPW group with the control group [hazard ratio (HR): 0.77 and confidence interval (CI): 0.47-1.25]. After radiofrequency ablation, the WPW group had a significantly higher risk of atrial fibrillation than the control group (HR: 4.77 and CI: 3.05-7.43). Atrial fibrillation prior to ablation (HR: 4.66 and CI: 2.09-10.41) and age over 50 years (HR: 9.79 and CI: 4.29-22.36) at the time of ablation were independent risk factors for post-ablation atrial fibrillation in the WPW group.CONCLUSION: Patients with radiofrequency ablation-treated WPW syndrome have a post-ablation mortality that is similar to the background population. The risk of atrial fibrillation remains high after radiofrequency ablation of the WPW syndrome.

Background: The epidermal growth factor receptor (EGFR) is overexpressed in colorectal cancer (CRC), and is correlated with poor prognosis, making it an attractive target for monoclonal antibody (mAb) therapy. A component of the therapeutic efficacy of IgG1 mAbs is their stimulation of antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells bearing the CD16 receptor. As NK cells are functionally impaired in cancer patients and may be further compromised upon chemotherapy, it is crucial to assess whether immunotherapeutic strategies aimed at further enhancing ADCC are viable. Methods: CRC patients before, during and after chemotherapy were immunophenotyped by flow cytometry for major white blood cell populations. ADCC-independent NK cell functionality was assessed in cytotoxicity assays against K562 cells. ADCC-dependent killing of EGFR+ A431 cancer cells by NK cells was measured with a degranulation assay where ADCC was induced by GA201, an anti-EGFR mAb glyco-engineered to enhance ADCC. Results: Here, we confirm the observation that NK cells in cancer patients are dysfunctional. However, GA201 was able to induce robust NK cell-dependent cytotoxicity in CRC patient NK cells, effectively overcoming their impairment. Conclusions: These findings support the evaluation of the therapeutic potential of GA201 in combination with chemotherapy in CRC patients.

We report the first preclinical in vitro and in vivo comparison of GA101 (obinutuzumab), a novel glycoengineered type II CD20 monoclonal antibody, with rituximab and ofatumumab, the two currently approved type I CD20 antibodies. The three antibodies were compared in assays measuring direct cell death (AnnexinV/PI staining and time-lapse microscopy), complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and internalization. The models used for the comparison of their activity in vivo were SU-DHL4 and RL xenografts. GA101 was found to be superior to rituximab and ofatumumab in the induction of direct cell death (independent of mechanical manipulation required for cell aggregate disruption formed by antibody treatment), whereas it was 10 to 1,000 times less potent in mediating CDC. GA101 showed superior activity to rituximab and ofatumumab in ADCC and whole-blood B-cell depletion assays, and was comparable with these two in ADCP. GA101 also showed slower internalization rate upon binding to CD20 than rituximab and ofatumumab. In vivo, GA101 induced a strong antitumor effect, including complete tumor remission in the SU-DHL4 model and overall superior efficacy compared with both rituximab and ofatumumab. When rituximab-pretreated animals were used, second-line treatment with GA101 was still able to control tumor progression, whereas tumors escaped rituximab treatment. Taken together, the preclinical data show that the glyoengineered type II CD20 antibody GA101 is differentiated from the two approved type I CD20 antibodies rituximab and ofatumumab by its overall preclinical activity, further supporting its clinical investigation. Mol Cancer Ther; 12(10); 2031–42. ©2013 AACR.

Homogeneous charge compression ignition (HCCI) holds promise for reduced emissions and increased efficiency compared to conventional internal combustion engines. As HCCI lacks direct actuation over the combustion phasing, much work has been devoted to designing controllers capable of set-point tracking and disturbance rejection. This paper presents results on model predictive control (MPC) of the combustion phasing in an HCCI engine based on a hybrid model formulation composed of several linearizations of a physics-based nonlinear model. The explicit representation of the MPC was implemented experimentally and the performance during set point changes was compared to that of a switched state feedback controller. The hybrid MPC produced smoother transients without overshoot when the set point change traversed several linearizations.

Purpose: Anti-EGF receptor (EGFR) antibodies and small-molecule tyrosine kinase inhibitors have shown activity in epithelial tumors; however, agents that work by blocking the EGFR growth signal are ineffective when the oncogenic stimulus arises downstream, such as in tumors with KRAS mutations. Antibodies of the IgG1 subclass can also kill tumor cells directly through antibody-dependent cell-mediated cytotoxicity (ADCC), and the efficacy of this is determined by the interaction of the Fc portion of the target cell–bound antibody and Fc receptors present on immune effector cells. Experimental Design: We report the development of GA201, a novel anti-EGFR monoclonal antibody with enhanced ADCC properties. GA201 was derived by humanization of the rat ICR62 antibody. The Fc region of GA201 was glycoengineered to contain bisected, afucosylated carbohydrates for enhanced binding to FcγRIIIA. Results: In vitro binding of GA201 to EGFR inhibited EGF ligand binding, EGFR/HER2 heterodimerization, downstream signaling, and cell proliferation to a similar extent as cetuximab. However, GA201 exhibited superior binding to both the low- and high-affinity variants of FcγRIIIA. This resulted in significantly enhanced induction of ADCC compared with cetuximab against both KRAS-wild-type and -mutant tumor cells lines. This enhanced ADCC translated into superior in vivo efficacy in a series of mouse xenograft models. Efficacy of GA201 was further increased when administered in combination with chemotherapy (irinotecan). Conclusions: These data suggest that GA201 may be more effective than cetuximab in patients with EGFR-positive solid tumors and may also represent a first-in-class treatment of patients with KRAS-mutated tumors. Clin Cancer Res; 19(5); 1126–38. ©2012 AACR.

Envelope control has been implemented successfully in aircraft for over a decade to assist pilots in stabilising their planes. With current advances in sideslip angle and friction coefficient estimation, envelope control can now be applied to the automotive industry as well. Using full state estimation of yaw rate and sideslip angle, stability controllers can assist the driver by keeping the vehicle within a safe region of the planar state space. This paper discusses the physical phenomena that must be taken into account when choosing an envelope and details a specific choice of envelope comprised of the yaw acceleration nullcline and the maximum rear slip angle limits. The vehicle is kept within the envelope using a computationally simple sliding surface control scheme. Experimental data show the success of the controller, which is implemented on a vehicle through the use of steer-by-wire.

Homogeneous charge compression ignition (HCCI) presents new challenges in combustion phasing control due to the lack of direct ignition trigger. In addition, recompression HCCI possesses cycle-to-cycle coupling through trapping a large portion of the exhaust gas in the cylinder. This paper examines the change in the cycle-to-cycle coupling around different operating points in recompression HCCI and show that there are three qualitative types of temperature dynamics: smooth decaying when combustion phasing is early, oscillatory when phasing is late, and strongly converging with moderate combustion phasing. As a result, a three region switching linear model that combines three linearized models can capture the qualitative change in system characteristics. Based on this model, a three region switching controller is designed and shown in experiments that it can track a wide range of desired combustion phasing and improve the variance of combustion phasing over open-loop operations. In the last part of this paper, two semi-definite programming (SDP) formulations are presented to prove the stability of the switching control/model framework. (C) 2012 Elsevier Ltd. All rights reserved.

Leveraging new technology in vehicle actuation and sensing, the authors present a control framework for obstacle avoidance and stability control using safe driving envelopes. One of these envelopes is defined by the vehicle handling limits and the other is based on spatial limitations imposed by the environment. A Model Predictive Control (MPC) scheme determines at each time step if the current driver command allows for a safe vehicle trajectory within these two envelopes, intervening only when such a trajectory does not exist. In this way, the controller shares control with the driver in a minimally invasive manner while allowing the driver access to the full capabilities of the vehicle.

Drivers use steering feel to obtain information about the road and tire dynamics that aids them in driving tasks like curve negotiation. Steer-by-wire vehicles, due to the mechanical decoupling of the front tires and handwheel, do not have any inherent steering feel and, as a result, drivers lose this important source of driving feedback. Creating an artificial steering feel in these vehicles allows the driver to continue to access this useful information. This paper proposes using a simple vehicle model simulation to design a realistic artificial steering feel. Conventional steering feel performance measures are used to evaluate and tune an artificial steering feel to obtain desired characteristics. A steer-by-wire vehicle performing a dynamic weave test is used to obtain experimental performance measures for this designed feel and a comparison is made with the simulated performance measures to verify the validity of the simple model simulation design technique proposed.

// Martin Pool 1 , Arjan Kol 1 , Marjolijn N. Lub-de Hooge 2, 3 , Christian A. Gerdes 4 , Steven de Jong 1 , Elisabeth G.E. de Vries 1 , Anton G.T. Terwisscha van Scheltinga 2 1 Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 2 Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 3 Department of Nuclear Medicine and Molecular Imaging, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 4 Department of Roche Pharma Research and Early Development, Roche Innovation Center Zurich, Schlieren, Switzerland Correspondence to: Anton G.T. Terwisscha van Scheltinga, email: a.g.t.terwisscha.van.scheltinga@umcg.nl Keywords: imgatuzumab, EGFR, 89 Zr, immunoPET, shedding Received: January 06, 2016 Accepted: August 27, 2016 Published: September 02, 2016 ABSTRACT Preclinical positron emission tomography (PET) imaging revealed a mismatch between in vivo epidermal growth factor receptor (EGFR) expression and EGFR antibody tracer tumor uptake. Shed EGFR ectodomain (sEGFR), which is present in cancer patient sera, can potentially bind tracer and therefore influence tracer kinetics. To optimize EGFR-PET, we examined the influence of sEGFR levels on tracer kinetics and tumor uptake of EGFR monoclonal antibody 89 Zr-imgatuzumab in varying xenograft models. Human cancer cell lines A431 (EGFR overexpressing, epidermoid), A549 and H441 (both EGFR medium expressing, non-small cell lung cancer) were xenografted in mice. Xenografted mice received 10, 25 or 160 μg 89 Zr-imgatuzumab, co-injected with equal doses 111 In-IgG control. MicroPET scans were made 24, 72 and 144 h post injection, followed by biodistribution analysis. sEGFR levels in liver and plasma samples were determined by ELISA. 89 Zr-imgatuzumab uptake in A431 tumors was highest (29.8 ± 5.4 %ID/g) in the 160 μg dose group. Contrary, highest uptake in A549 and H441 tumors was found at the lowest (10 μg) 89 Zr-imgatuzumab dose. High 89 Zr-imgatuzumab liver accumulation was found in A431 xenografted mice, which decreased with antibody dose increments. 89 Zr-imgatuzumab liver uptake in A549 and H441 xenografted mice was low at all doses. sEGFR levels in liver and plasma of A431 bearing mice were up to 1000-fold higher than levels found in A549, H441 and non-tumor xenografted mice. 89 Zr-imgatuzumab effectively visualizes EGFR-expressing tumors. High sEGFR levels can redirect 89 Zr-imgatuzumab to the liver, in which case tumor visualization can be improved by increasing tracer antibody dose.

Anti-CD20 monoclonal antibodies (mAbs) represent an effective treatment for a number of B cell malignancies and autoimmune disorders. Glycoengineering of anti-CD20mAb may contribute to increased anti-tumor efficacy through enhanced antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADP) as reported by in vitro studies. However, where and how glycoengineered Ab may potentiate therapeutic responses in vivo is yet to be elucidated. Here, we have performed mouse liver transplants to demonstrate that the liver is sufficient to mediate systemic B cells depletion after anti-CD20 treatment. Relying on intravital two-photon imaging of human CD20-expressing mice, we provide evidence that ADP by Kupffer cells (KC) is a major mechanism for rituximab-mediated B cell depletion. Notably, a glycoengineered anti-mouse CD20 Ab but not its wild-type counterpart triggered potent KC-mediated B cell depletion at low doses. Finally, distinct thresholds for KC phagocytosis were also observed for GA101 (obinutuzumab), a humanized glycoengineered type II anti-CD20 Ab and rituximab. Thus, we propose that enhanced phagocytosis of circulating B cells by KC represents an important in vivo mechanism underlying the improved activity of glycoengineered anti-CD20 mAbs.

Vehicles in the foreseeable future will be required to transition between autonomous driving (without human involvement) and full human control. During this transition period, the human, who has not been actively engaged in the driving process, must resume the motor control necessary to steer the car. The in-car study presented here demonstrates that when human drivers are presented with a steering behavior that is different from the last time they were in control, specifically the ratio of hand wheel angle to road wheel angle (emulating a change in vehicle speed), they undergo a significant period of adaptation before they return to their previous steering behavior. However, drivers do not require an adaptation period to return to previous driving behavior after changes in steering torque. These findings have implications for the design of vehicles that transition from automated to manual driving and for understanding of human motor control in real-world tasks.

Ethical frameworks and principles from philosophy have long been used to characterize human behavior. As driving is transitioning from human control to automated control, these ethical frameworks can be used to guide engineering design decisions for autonomous vehicles in a responsible manner. In particular, moral regulation provides two methods for guiding behavior. Proscriptive strategies emphasize rules, transgressions, and forbidding rule violation. Prescriptive strategies encourage achievement of goals. These two principles have been shown to map to human behavior regulation in approach and avoidance. These concepts have a natural parallel to driving strategies, and thus to differing outlooks on programming automated vehicles. In this paper, we apply proscriptive and prescriptive strategies to a model predictive control framework for an automated vehicle. Two scenarios featuring the ego vehicle navigating with obstacles in a roadway are used to elicit the resulting and differing vehicle behavior when either approach is used.

This editorial refers to ‘Catheter ablation for atrial fibrillation is associated with lower incidence of stroke and death: data from Swedish health registries’†, by L. Friberg et al . on page 2478 . Catheter ablation is as an effective treatment for reducing arrhythmia burden and improving quality of life in patients with symptomatic atrial fibrillation (AF),1,2 and most effective in patients with paroxysmal AF. Many patients will experience symptomatic or asymptomatic episodes of AF after catheter ablation, and, in most patients with AF, catheter ablation cannot be considered curative.3,4 Population studies indicate that AF is closely associated with a higher risk of stroke and increased mortality.5 Recent data support paroxysmal AF as being associated with lower stroke risk than permanent AF.6 Theoretically, performing catheter ablation and reducing AF burden therefore may improve patients' outcome with respect to stroke and death. Some observational studies support this, even though it was never supported by any randomized controlled trial. In contrast, it is well documented that a rhythm control strategy by antiarrhythmic drug therapy is not superior to rate control therapy with respect to survival. …

Purpose: CEA TCB is a novel IgG-based T-cell bispecific (TCB) antibody for the treatment of CEA-expressing solid tumors currently in phase I clinical trials (NCT02324257). Its format incorporates bivalent binding to CEA, a head-to-tail fusion of CEA- and CD3e-binding Fab domains and an engineered Fc region with completely abolished binding to FcγRs and C1q. The study provides novel mechanistic insights into the activity and mode of action of CEA TCB. Experimental Design: CEA TCB activity was characterized on 110 cell lines in vitro and in xenograft tumor models in vivo using NOG mice engrafted with human peripheral blood mononuclear cells. Results: Simultaneous binding of CEA TCB to tumor and T cells leads to formation of immunologic synapses, T-cell activation, secretion of cytotoxic granules, and tumor cell lysis. CEA TCB activity strongly correlates with CEA expression, with higher potency observed in highly CEA-expressing tumor cells and a threshold of approximately 10,000 CEA-binding sites/cell, which allows distinguishing between high- and low-CEA–expressing tumor and primary epithelial cells, respectively. Genetic factors do not affect CEA TCB activity confirming that CEA expression level is the strongest predictor of CEA TCB activity. In vivo, CEA TCB induces regression of CEA-expressing xenograft tumors with variable amounts of immune cell infiltrate, leads to increased frequency of activated T cells, and converts PD-L1 negative into PD-L1–positive tumors. Conclusions: CEA TCB is a novel generation TCB displaying potent antitumor activity; it is efficacious in poorly infiltrated tumors where it increases T-cell infiltration and generates a highly inflamed tumor microenvironment. Clin Cancer Res; 22(13); 3286–97. ©2016 AACR.

We implanted a Medtronic Micra Transcatheter Pacing System (TPS) using standard technique, but after cutting the tether, a slight resistance was felt when the tether was pulled back. Subsequently, the electrical properties of the system were unacceptable. In order to retrieve the TPS, a …

This book takes a look at fully automated, autonomous vehicles and discusses many open questions: How can autonomous vehicles be integrated into the current transportation system with diverse users and human drivers? Where do automated vehicles fall under current legal frameworks? What risks are associated with automation and how will society respond to these risks? How will the marketplace react to automated vehicles and what changes may be necessary for companies? Experts from Germany and the United States define key societal, engineering, and mobility issues related to the automation of vehicles. They discuss the decisions programmers of automated vehicles must make to enable vehicles to perceive their environment, interact with other road users, and choose actions that may have ethical consequences. The authors further identify expectations and concerns that will form the basis for individual and societal acceptance of autonomous driving. While the safety benefits of such vehicles are tremendous, the authors demonstrate that these benefits will only be achieved if vehicles have an appropriate safety concept at the heart of their design. Realizing the potential of automated vehicles to reorganize traffic and transform mobility of people and goods requires similar care in the design of vehicles and networks. By covering all ofthese topics, the book aims to provide a current, comprehensive, and scientifically sound treatment of the emerging field of autonomous driving".

In this study we present novel bispecific antibodies that simultaneously target the insulin-like growth factor receptor type I (IGF-1R) and epidermal growth factor receptor (EGFR). For this purpose disulfide stabilized scFv domains of the EGFR/ADCC antibody GA201 were fused via serine-glycine connectors to the C-terminus of the heavy (XGFR2) or light chain (XGFR4), or the N-termini of the light (XGFR5) or heavy chain (XGFR3) of the IGF-1R antibody R1507 as parental IgG1 antibody. The resulting bispecific IGF-1R-EGFR antibodies XGFR2, XGFR3 and XGFR4 were successfully generated with yields and stability comparable to conventional IgG1 antibodies. They effectively inhibited IGF-1R and EGFR phosphorylation and 3D proliferation of H322M and H460M2 tumor cells, induced strong down-modulation of IGF-1R as well as enhanced EGFR down-modulation compared to the parental EGFR antibody GA201 and were ADCC competent. The bispecific XGFR derivatives showed a strong format dependent influence of N- or C-terminal heavy and light chain scFv attachment on ADCC activity and an increase in receptor downregulation over the parental combination in vitro. XGFR2 and XGFR4 were selected for in vivo evaluation and showed potent anti-tumoral efficacy comparable to the combination of monospecific IGF-1R and EGFR antibodies in subcutaneous BxPC3 and H322M xenograft models. In summary, we have managed to overcome issues of stability and productivity of bispecific antibodies, discovered important antibody fusion protein design related differences on ADCC activity and receptor downmodulation and show that IGF-1R-EGFR antibodies represent an attractive therapeutic strategy to simultaneously target two key components de-regulated in multiple cancer types, with the ultimate goal to avoid the formation of resistance to therapy.

Control of work output and combustion phasing on a Homogeneous Charge Compression Ignition (HCCI) engine is essential to realize the benefits of superior efficiency and emissions. This paper presents a model predictive control approach for cycle-by-cycle control of HCCI while respecting constraints on actuators that might exist on a production implementation. The strategy is based on a physical model developed in previous work and uses valve actuation and split fuel injection to achieve the control objectives. In addition, it considers constraints on air–fuel ratio, ensuring that the system stays away from very lean or rich regions. Simulation and experimental results show that the controller works well over a range of conditions, and demonstrate the potential of this approach as a practical cycle-by-cycle control strategy for HCCI.

Understanding how a race car driver controls a vehicle at its friction limits can provide insights into the development of vehicle safety systems. In this paper, a race car driver's behaviour inspires the design of an autonomous racing controller. The resulting controller uses the vehicle's centre of percussion (COP) to design feedforward and feedback steering. At the COP, the effects of rotation and translation from the rear tire force cancel each other out; consequently, the feedforward steering command is robust to the disturbances from the rear tire force. Using the COP also simplifies the equations of motion, as the vehicle's lateral motion is decoupled from the vehicle's yaw motion and highlights the challenge of controlling a vehicle when the rear tires are highly saturated. The resulting dynamics can be controlled with a linear state feedback based on a lane-keeping system with additional yaw damping. Utilising Lyapunov theory, the closed-loop system is shown to remain stable even when the rear tires are highly saturated. The experimental results demonstrate that an autonomous vehicle can operate at its limits while maintaining a minimal lateral error.

The success of Electronic Stability Control (ESC) has demonstrated the potential life-saving benefits of vehicle control systems. Lanekeeping presents an obvious next step in vehicle control, but the performance of such systems must be guaranteed before lanekeeping can be viewed as a safety feature. This paper demonstrates that simple lookahead control schemes for lanekeeping are provably robust even at the limits of tire adhesion. By responding to the heading error relative to the desired path, these schemes provide the countersteer behavior necessary to compensate for rear tire saturation and stabilize the vehicle. Using a Lyapunov-based analysis, vehicle stability can be proven even with a highly saturated tire. Taking this a step further by developing a desired path based on the racing line, this lookahead controller can be coupled with longitudinal control based on path position and wheel slip to create an autonomous racecar. The performance of this algorithm shows the potential for lanekeeping control that can truly assist even the best drivers.

This paper presents simple analytical techniques that are used to understand and control high sideslip drift manoeuvres of road vehicles. These are manoeuvres in which a skilled driver stabilises a vehicle beyond its limits of handling, an operating regime responsible for major safety concerns in everyday driving. An analysis of the equilibria of a bicycle model with nonlinear tyres reveals the existence of unstable 'drift equilibria' corresponding to cornering at high sideslip angle in a countersteer configuration. Equipped with this information, linearisation about a desired drift equilibrium is used to design a controller that stabilises the vehicle at the equilibrium. The controller is subsequently implemented on a steer- and drive-by-wire testbed and successfully used to achieve autonomous drifts.

A framework for modeling late-phasing homogeneous charge, compression ignition (HCCI) combustion shows that combustion instability can be represented as a negative real-axis pole in a discrete-time linearized system. A simple, nonlinear model of the HCCI process presented in previous work effectively captures decreases in heat transfer at late-phasing HCCI points. These decreases in heat transfer result in highly oscillatory responses of combustion phasing at late-phasing HCCI points. Root loci generated by linearizing the nonlinear model at different operating conditions illustrate that a system pole moves from the origin at a nominal case onto the negative real axis for the late-phasing case. Finally, simple proportional control of exhaust valve closing, based on output feedback, demonstrates sufficient reduction in drastic swings in combustion phasing and indicated mean effective pressure.

As manufacturers offer glimpses of their future vehicles, it is apparent that computational power and sensory information will significantly increase. These advances offer the opportunity to design a controller that leverages new information to improve stability while attaining a higher level of coordination with the driver. In this paper, the authors present an approach that utilizes axle slip angles to define an envelope in which the vehicle behavior is stable and predictable. A linear model predictive controller using front active steering is developed. Experimental results using a steer-by-wire test vehicle are presented to demonstrate the functionality of the controller. Analysis of the results includes discussion of the limitations of the linear controller in controlling the vehicle at the limits of handling and how disturbances and unmodeled driver input can cause the slip angles to deviate from this envelope.

Knowledge of the vehicle's lateral handling limits is important for vehicle control systems which aim to enhance vehicle handling and passenger safety. This paper presents a model-based estimation method that utilizes pneumatic trail information in steering torque to identify a vehicle's lateral handling limits, which are defined by the tire slip angle and peak lateral force limits. This method uses measurements available on many current production vehicles. Most importantly, it takes advantage of the early friction information encoded in the tire pneumatic trail. Pneumatic trail decreases as a function of the tire parameters even in the linear handling region, enabling early detection of the limits before they are reached. Experimental results on an independent front steering steer-by-wire research vehicle demonstrate the observer's ability to provide accurate real-time estimates of tire slip angle up to the limits of handling. Testing conditions include maneuvers performed on dry, flat paved road, as well as on lower-friction, dry gravel.

This paper presents the design and experimental implementation of a dynamic surface controller for sideslip angle during autonomous drifting of a rear wheel drive vehicle. In this design, yaw rate is used as a synthetic input to control the vehicle's sideslip dynamics, and yaw rate is in turn controlled through coordination of the front tire lateral force (steering) and rear tire longitudinal force (drive). This input coordination is designed to increase rear tire saturation in order to maintain controllability of the vehicle via the front tire lateral force. This reflects a stability-controllability tradeoff that is characteristic of the steady state conditions corresponding to drifting and could have interesting applications to trajectory control when a vehicle's handling limits have been exceeded. The control technique has been implemented on P1, a student-built by-wire testbed, and shown to successfully achieve robust, sustained drifts.

While today's ESC systems are effective, they are predominantly reactive, offering control effort only once the vehicle has become unstable. This paper introduces a new method of vehicle envelope control that proactively utilizes a sliding surface to keep the vehicle within a stable region. Experimental results are shown, using a steer-by-wire electric vehicle testbed to augment the driver's input through steering commands. The results demonstrate that the controller is successful in stabilizing the vehicle on a variable friction gravel surface.