Though in its original concept a robot was conceived to have some human-like shape, most robots now in use have specific industrial purposes and do not closely resemble humans. Nevertheless, robots that resemble human form in some way have continued to be introduced. They are called anthropomorphic robots. The fact that the user interface to all robots is now highly mediated means that the form of the user interface is not necessarily connected to the robots form, human or otherwise. Consequently, the unique way the design of anthropomorphic robots affects their user interaction is through their general appearance and the way they move. These robots human-like appearance acts as a kind of generalized predictor that gives its operators, and those with whom they may directly work, the expectation that they will behave to some extent like a human. This expectation is especially prominent for interactions with social robots, which are built to enhance it. Often interaction with them may be mainly cognitive because they are not necessarily kinematically intricate enough for complex physical interaction. Their body movement, for example, may be limited to simple wheeled locomotion. An anthropomorphic robot with human form, however, can be kinematically complex and designed, for example, to reproduce the details of human limb, torso, and head movement. Because of the mediated nature of robot control, there remains in general no necessary connection between the specific form of user interface and the anthropomorphic form of the robot. But their anthropomorphic kinematics and dynamics imply that the impact of their design shows up in the way the robot moves. The central finding of this report is that the control of this motion is a basic design element through which the anthropomorphic form can affect user interaction. In particular, designers of anthropomorphic robots can take advantage of the inherent human-like movement to 1) improve the users direct manual control over robot limbs and body positions, 2) improve users ability to detect anomalous robot behavior which could signal malfunction, and 3) enable users to be better able to infer the intent of robot movement. These three benefits of anthropomorphic design are inherent implications of the anthropomorphic form but they need to be recognized by designers as part of anthropomorphic design and explicitly enhanced to maximize their beneficial impact. Examples of such enhancements are provided in this report. If implemented, these benefits of anthropomorphic design can help reduce the risk of Inadequate Design of Human and Automation Robotic Integration (HARI) associated with the HARI-01 gap by providing efficient and dexterous operator control over robots and by improving operator ability to detect malfunctions and understand the intention of robot movement.

/pdf/anthropomorphic-robot-design-and-user-interaction-associated-lmlxj3n80v.pdf

Anthropomorphic Robot Design and User Interaction Associated with Motion

Getting the right combination to break the epigenetic code

Simple Summary Histone deacetylase (HDAC) inhibitors are anti-cancer agents that have demonstrated efficacy in hematologic malignancies; however, the utility of available agents is limited, owing to narrow therapeutic indices and suboptimal isoform selectivity. Bocodepsin (OKI-179) is a novel, orally bioavailable, Class I-targeting depsipeptide HDAC inhibitor with promising anti-cancer activity in preclinical solid tumor models. In this first-in-human phase I clinical study, we report the safety and tolerability of OKI-179 administered orally daily with intermittent and continuous dosing schedules. OKI-179 was well tolerated with low rates of high-grade adverse events, supporting the potential for the successful combination of OKI-179 with other targeted anti-cancer agents. OKI-179 is currently being investigated in combination with the MEK inhibitor binimetinib in patients with NRAS-mutated melanoma. Abstract (1) Background: Histone deacetylases (HDACs) play a critical role in epigenetic signaling in cancer; however, available HDAC inhibitors have limited therapeutic windows and suboptimal pharmacokinetics (PK). This first-in-human phase I dose escalation study evaluated the safety, PK, pharmacodynamics (PDx), and efficacy of the oral Class I-targeting HDAC inhibitor bocodepsin (OKI-179). (2) Patients and Methods: Patients (n = 34) with advanced solid tumors were treated with OKI-179 orally once daily in three schedules: 4 days on 3 days off (4:3), 5 days on 2 days off (5:2), or continuous in 21-day cycles until disease progression or unacceptable toxicity. Single-patient escalation cohorts followed a standard 3 + 3 design. (3) Results: The mean duration of treatment was 81.2 (range 11–447) days. The most frequent adverse events in all patients were nausea (70.6%), fatigue (47.1%), and thrombocytopenia (41.2%). The maximum tolerated dose (MTD) of OKI-179 was 450 mg with 4:3 and 200 mg with continuous dosing. Dose-limiting toxicities included decreased platelet count and nausea. Prolonged disease control was observed, including two patients with platinum-resistant ovarian cancer. Systemic exposure to the active metabolite exceeded the preclinical efficacy threshold at doses lower than the MTD and was temporally associated with increased histone acetylation in circulating T cells. (4) Conclusions: OKI-179 has a manageable safety profile at the recommended phase 2 dose (RP2D) of 300 mg daily on a 4:3 schedule with prophylactic oral antiemetics. OKI-179 is currently being investigated with the MEK inhibitor binimetinib in patients with NRAS-mutated melanoma in the phase 2 Nautilus trial.

First-in-Human Dose-Escalation Study of the Novel Oral Depsipeptide Class I-Targeting HDAC Inhibitor Bocodepsin (OKI-179) in Patients with Advanced Solid Tumors

Our research achievements under the NASA-JSC grant contributed significantly in the following areas. Multi-agent based robot control architecture called the Intelligent Machine Architecture (IMA) : The Vanderbilt team received a Space Act Award for this research from NASA JSC in October 2004. Cognitive Control and the Self Agent : Cognitive control in human is the ability to consciously manipulate thoughts and behaviors using attention to deal with conflicting goals and demands. We have been updating the IMA Self Agent towards this goal. If opportunity arises, we would like to work with NASA to empower Robonaut to do cognitive control. Applications 1. SES for Robonaut, 2. Robonaut Fault Diagnostic System, 3. ISAC Behavior Generation and Learning, 4. Segway Research.

/pdf/acquisition-of-autonomous-behaviors-by-robotic-assistants-38v0unjyw3.pdf

Acquisition of Autonomous Behaviors by Robotic Assistants


 Activating RAS pathway mutations are found in >30% of human tumors, and often associated with poor outcomes. While RAS-pathway targeted drugs have been approved, their activity as single-agents remains modest, supporting the need for rational targeted combinations to improve patient outcomes. Multiple studies have proposed a chemical synthetic lethality between Class I histone deacetylase inhibitors (HDACi), and RAS-pathway inhibitors in RAS-pathway mutated models. This synthetic lethality occurs due to a combined effect to inhibit double-stranded (ds) DNA repair and other survival pathways to drive apoptosis and tumor regressions. The use of HDACi in solid tumors and combinations has been challenged by poor potency, selectivity, safety and convenience, highlighting the need for a better HDACi in the clinic. OKI-179, a novel largazole derivative, is a potent, Class I-selective, oral HDACi that has completed Ph 1 clinical trials in patients with solid tumors. The clinical profile shows the potential to achieve exposure consistent with preclinical activity with strong pharmacodynamic activity at tolerated doses, supporting the development of OKI-179 in solid tumor combinations. Here we show synergistic activity of combining OKI-179 with the MEK inhibitor binimetinib (bini) or bini + RAF-inhibitor encorafenib (enco/bini) in both CDX and PDX models of NRAS-mutated melanoma and BRAF-mutated colorectal cancer (CRC). In vitro, combining OKI-179 with bini in SKMEL-2 NRASMT melanoma cells shows strong synergy, inducing a significant increase in cell death compared to single agents at clinically achievable drug concentrations. This activity was associated with a significant increase in gH2AX, a marker of ds DNA breaks, and apoptosis as measured by cleaved PARP. The activity of this combination was further investigated in vivo in established PDx models of NRAS-mutant melanoma, MEL278 and MM415. As single agents, both bini (3.5 mg/kg PO bid,21 d) and OKI-179 (80 mg/kg PO; 5/wk x 3 wk), doses that mimic the clinical exposure of these molecules, showed modest tumor growth inhibition (TGI). Combining bini and OKI-179 induced significantly greater TGI, including regression in 28-50% of the tumors, as compared to 0-6% for bini alone. A similar outcome was also observed in HT29 tumors (BRAFmt CRC) where the combination of OKI-179 and enco/bini showed regression in 50% of tumors, compared to 0% for OKI-179 or enco/bini alone. This supports the potential for additive efficacy of HDACi combined with RAS-pathway inhibitors across RAS-pathway mutations and tumor types. No additivity was observed in only one model (CRC563 - BRAFmt). These data show the potential for OKI-179 to synergize with RAS-pathway inhibitors across multiple indications. To investigate, a Phase1b/2 trial of OKI-179 with binimetinib in NRAS melanoma will initiate in early 2022.
 Citation Format: Richard Woessner, Patrice Lee, Eric Brown, Duncan H. Walker, James Winkler, Tony Piscopio. Theclass Iselective, oral HDAC inhibitor OKI-179 increases tumor regressions when combined with the MEK inhibitor binimetinib inmodels of NRAS melanoma [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 LB204.

Abstract LB204: Theclass Iselective, oral HDAC inhibitor OKI-179 increases tumor regressions when combined with the MEK inhibitor binimetinib inmodels of NRAS melanoma

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Acquisition of Autonomous Behaviors by Robotic Assistants

Abstract LB204: Theclass Iselective, oral HDAC inhibitor OKI-179 increases tumor regressions when combined with the MEK inhibitor binimetinib inmodels of NRAS melanoma