Bayesian Disturbance Injection: Robust Imitation Learning of Flexible Policies

Scenarios requiring humans to choose from multiple seemingly optimal actions are commonplace, however standard imitation learning often fails to capture this behavior. Instead, an over-reliance on replicating expert actions induces inflexible and unstable policies, leading to poor generalizability in an application. To address the problem, this paper presents the first imitation learning framework that incorporates Bayesian variational inference for learning flexible non-parametric multi-action policies, while simultaneously robustifying the policies against sources of error, by introducing and optimizing disturbances to create a richer demonstration dataset. This combinatorial approach forces the policy to adapt to challenging situations, enabling stable multi-action policies to be learned efficiently. The effectiveness of our proposed method is evaluated through simulations and real-robot experiments for a table-sweep task using the UR3 6-DOF robotic arm. Results show that, through improved flexibility and robustness, the learning performance and control safety are better than comparison methods.Comment: 7 pages, Accepted by the 2021 International Conference on Robotics and Automation (ICRA 2021

Bayesian Disturbance Injection: Robust Imitation Learning of Flexible Policies for Robot Manipulation

Humans demonstrate a variety of interesting behavioral characteristics when performing tasks, such as selecting between seemingly equivalent optimal actions, performing recovery actions when deviating from the optimal trajectory, or moderating actions in response to sensed risks. However, imitation learning, which attempts to teach robots to perform these same tasks from observations of human demonstrations, often fails to capture such behavior. Specifically, commonly used learning algorithms embody inherent contradictions between the learning assumptions (e.g., single optimal action) and actual human behavior (e.g., multiple optimal actions), thereby limiting robot generalizability, applicability, and demonstration feasibility. To address this, this paper proposes designing imitation learning algorithms with a focus on utilizing human behavioral characteristics, thereby embodying principles for capturing and exploiting actual demonstrator behavioral characteristics. This paper presents the first imitation learning framework, Bayesian Disturbance Injection (BDI), that typifies human behavioral characteristics by incorporating model flexibility, robustification, and risk sensitivity. Bayesian inference is used to learn flexible non-parametric multi-action policies, while simultaneously robustifying policies by injecting risk-sensitive disturbances to induce human recovery action and ensuring demonstration feasibility. Our method is evaluated through risk-sensitive simulations and real-robot experiments (e.g., table-sweep task, shaft-reach task and shaft-insertion task) using the UR5e 6-DOF robotic arm, to demonstrate the improved characterisation of behavior. Results show significant improvement in task performance, through improved flexibility, robustness as well as demonstration feasibility.Comment: 69 pages, 9 figures, accepted by Elsevier Neural Networks - Journa

Role of CD10 in the Metastasis of Colorectal Cancer to the Liver.

CD10 is a widely expressed endopeptidase that is present in human colorectal cancer (CRC), which shows a high frequency of liver metastasis. CD10 expression in CRC cells is associated with liver metastasis in rodent models, and CD10 expression enhances the phosphorylation of epidermal growth factor (EGF) receptor (EGFR) and extracellular signalregulated kinase (ERK) l/2. Met-enkephalin (MENK), a CD10 substrate, activates its specific receptor δ-opioid receptor (DOR), which is expressed in CRCs. DOR is a partial agonist of ERK1/2, which suppresses EGF-induced phosphorylation of EGFR and ERK1/2. CD10 retains EGF-induced EGFR activation by degrading MENK. Paradoxically, CRCs express MENK at a high frequency. Since MENK suppresses T lymphocytes, CD10-expressing CRCs can escape from T-cell immunity without exhibiting auto-inhibition. CD10 is strongly associated with the metastasis of CRCs to the liver via an immunosuppressive mechanism. Additionally, CD10 may be an excellent serum marker for liver metastasis in patients with CRC and could represent a potential molecular target for antimetastatic treatment in patients with CRC

酸化型HMGB-1は間葉系幹細胞/間葉系細胞を介して大腸癌の転移性を促進する

High mobility group box-1 (HMGB1) is known to be a chemotactic factor for mesenchymal stem/stromal cells (MSCs), but the effect of post-translational modification on its function is not clear. In this study, we hypothesized that differences in the oxidation state of HMGB1 would lead to differences in the function of MSCs in cancer. In human colorectal cancer, MSCs infiltrating into the stroma were correlated with liver metastasis and serum HMGB1. In animal models, oxidized HMGB1 mobilized three-fold fewer MSCs to subcutaneous tumors compared with reduced HMGB1. Reduced HMGB1 inhibited the proliferation of mouse bone marrow MSCs (BM-MSCs) and induced differentiation into osteoblasts and vascular pericytes, whereas oxidized HMGB1 promoted proliferation and increased stemness, and no differentiation was observed. When BM-MSCs pretreated with oxidized HMGB1 were co-cultured with syngeneic cancer cells, cell proliferation and stemness of cancer cells were increased, and tumorigenesis and drug resistance were promoted. In contrast, co-culture with reduced HMGB1-pretreated BM-MSCs did not enhance stemness. In an animal orthotopic transplantation colorectal cancer model, oxidized HMGB1, but not reduced HMGB1, promoted liver metastasis with intratumoral MSC chemotaxis. Therefore, oxidized HMGB1 reprograms MSCs and promotes cancer malignancy. The oxidized HMGB1–MSC axis may be an important target for cancer therapy.博士（医学）・甲第874号・令和5年3月15

Efficacy of human resource development program for young industry personnel who will be involved in future medical device development

Background: Training next-generation personnel from small/medium enterprises (SMEs) is an urgent issue in promoting medical device research and development (R&D). Since 2014 we have engaged in governmentally funded human resource development program for medical/non-medical SMEs, and have assessed its effectiveness by analyzing self-evaluation of achievement level (SEAL) data obtained before and after the training course. Methods: Human resource development experts interviewed 34 key opinion leaders with deep knowledge of medical device R&D from industry, government, and academia. The skills required for R&D personnel were written down, and a set of skills was created by making a greatest common measure in the list of common elements among them. Using that skill sets, skill evaluations were conducted on trainees at “Osaka University Training Course,” twice before participation and after completion of the entire program using SEAL assessment. Results: There were 97 men and 25 women, with one-third in the’30 s. Among them, 61 participants (50%) were from R&D divisions, and 32 (26%) were from business/sales divisions. 94 (77%) were from medical SMEs, and 28 (23%) were from non-medical SMEs (new entry). After completing the training course, significant growth was observed in every item of both Soft and Hard skill sets. Especially in new entry SME members, a striking improvement was observed in practical medical knowledge to enhance communication with medical doctors (p < 0.0001). Conclusion: Our training course, though 7-day-short in total, showed that both Soft and Hard skills could be improved in young medical/non-medical SME members. Further assessment is needed to establish the necessary skill sets for our future partners from industries, to foster the creation of innovative medical devices through med-tech collaboration.The version of record of this article, first published in Surgical Endoscopy, is available online at Publisher’s website: https://doi.org/10.1007/s00464-023-10474-

胃癌におけるクローディン4標的化によるシスプラチン化学療法感受性の向上

Claudins are major tight-junction proteins that mediate cellular polarity and differentiation. The present study investigated whether the 4D3 antibody to the human CLDN4 extracellular domain (that we previously established) is capable of modulating chemotherapeutic sensitivity in gastric cancer (GC). The results of the present study showed that CLDN4 was overexpressed in 137 of the 192 analyzed GC cases, and that CLDN4 expression was retained in tumors of a lower histological grade (more differentiated), and/or those that were caudal-type homeobox protein 2 (CDX2)-positive, but was reduced in more highly undifferentiated, and CDX2-negative GC cases. The study also compared the synergic effects of combining 4D3 with CDDP treatment and knocking down CLDN4 expression in MKN74 and TMK-1 human GC cells. Co-treatment with 4D3 increased anti-tumor effects of CDDP, whereas CLDN4 knockdown did not. In the TMK-1 cells, non-tight junction CLDN4 associated with integrin β1, increasing stem cell-associated proteins via FAK-c-SRC signals. The anti-tumoral effect of CDDP and 4D3 was examined in a nude mouse subcutaneous tumor model. In the two GC cell lines, concurrent treatment with 4D3 and CDDP synergistically inhibited cell proliferation and increased tumor necrosis and apoptosis to a greater degree than CDDP treatment alone. These findings suggest that 4D3 might increase chemotherapeutic sensitivity by evoking structural disintegration of tight-junction CLDN4 expressed in gastric cancer.博士（医学）・甲第713号・令和元年6月26日Copyright: Nishiguchi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0 https://creativecommons.org/licenses/by/3.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

中鎖脂肪酸と糖質の併用摂取は癌関連骨格筋萎縮から保護する

Skeletal muscle volume is associated with prognosis of cancer patients. Maintenance of skeletal muscle is an essential concern in cancer treatment. In nutritional intervention, it is important to focus on differences in metabolism between tumor and skeletal muscle. We examined the influence of oral intake of glucose (0%, 10%, 50%) and 2% medium-chain fatty acid (lauric acid, LAA, C12:0) on tumor growth and skeletal muscle atrophy in mouse peritoneal metastasis models using CT26 mouse colon cancer cells and HT29 human colon cancer cells. After 2 weeks of experimental breeding, skeletal muscle and tumor were removed and analyzed. Glucose intake contributed to prevention of skeletal muscle atrophy in a sugar concentration-dependent way and also promoted tumor growth. LAA ingestion elevated the level of skeletal muscle protein and suppressed tumor growth by inducing tumor-selective oxidative stress production. When a combination of glucose and LAA was ingested, skeletal muscle mass increased and tumor growth was suppressed. Our results confirmed that although glucose is an important nutrient for the prevention of skeletal muscle atrophy, it may also foster tumor growth. However, the ingestion of LAA inhibited tumor growth, and its combination with glucose promoted skeletal muscle integrity and function, without stimulating tumor growth. These findings suggest novel strategies for the prevention of skeletal muscle atrophy.博士（医学）・甲第733号・令和2年3月16日© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License(https://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes

Increased fatty acyl saturation of phosphatidylinositol phosphates in prostate cancer progression

Phosphoinositides (PIPs) participate in many cellular processes, including cancer progression; however, the metabolic features of PIPs associated with prostate cancer (PCa) are unknown. We investigated PIPs profiles in PTEN-deficient prostate cancer cell lines, human prostate tissues obtained from patients with PCa and benign prostate hyperplasia (BPH) specimens using mass spectrometry. In immortalized normal human prostate PNT1B cells, PTEN deficiency increased phosphatidylinositol tris-phosphate (PIP3) and decreased phosphatidylinositol mono- and bis-phosphate (PIP1 and PIN2 consistent with PTEN\u27s functional role as a PI(3,4,5)P-3 3-phosphatase. In human prostate tissues, levels of total (sum of all acyl variants) phosphatidylinositol (PI) and PIP1 in PCa were significantly higher than in BPH, whereas PIP2 and PIP3 contents were significantly lower than in BPH. PCa patients had significantly higher proportion of PI, PIP1, and PIP2 with 0-2 double bonds in acyl chains than BPH patients. In subgroup analyses based on PCa aggressiveness, mean total levels of PI with 0-2 double bonds in acyl chains were significantly higher in patients with pathological stage T3 than in those with pathological stage T2. These data indicate that alteration of PIPs level and the saturation of acyl chains may be associated with the development and aggressiveness of prostate cancer, although it is unknown whether this alteration is causative

Effects of time-compressed speech training on multiple functional and structural neural mechanisms involving the left superior temporal gyrus

Time-compressed speech is an artificial form of rapidly presented speech. Training with time-compressed speech (TCSSL) in a second language leads to adaptation toward TCSSL. Here, we newly investigated the effects of 4 weeks of training with TCSSL on diverse cognitive functions and neural systems using the fractional amplitude of spontaneous low-frequency fluctuations (fALFF), resting-state functional connectivity (RSFC) with the left superior temporal gyrus (STG), fractional anisotropy (FA), and regional gray matter volume (rGMV) of young adults by magnetic resonance imaging. There were no significant differences in change of performance of measures of cognitive functions or second language skills after training with TCSSL compared with that of the active control group. However, compared with the active control group, training with TCSSL was associated with increased fALFF, RSFC, and FA and decreased rGMV involving areas in the left STG. These results lacked evidence of a far transfer effect of time-compressed speech training on a wide range of cognitive functions and second language skills in young adults. However, these results demonstrated effects of time-compressed speech training on gray and white matter structures as well as on resting-state intrinsic activity and connectivity involving the left STG, which plays a key role in listening comprehension