A Sliding Mode Control Architecture for Human-Manipulator Cooperative Surface Treatment Tasks

© 2018 IEEE. This paper presents a control architecture readily suitable for surface treatment tasks such as polishing, grinding, finishing or deburring as carried out by a human operator, with the added benefit of accuracy, recurrence and physical strength as administered by a robotic manipulator partner. The shared strategy effectively couples the human operator propioceptive abilities and fine skills through his interactions with the autonomous physical agent. The novel proposed control scheme is based on task prioritization and a non-conventional sliding mode control, which is considered to benefit from its inherent robustness and low computational cost. The system relies on two force sensors, one located between the last link of the robot and the surface treatment tool, and the other located in some place of the robot end-effector: the former is used to suitably accomplish the conditioning task, while the latter is used by the operator to manually guide the robotic tool. When the operator chooses to cease guiding the tool, the robot motion safely switches back to an automatic reference tracking. The paper presents the theories for the novel collaborative controller, whilst its effectiveness for robotic surface treatment is substantiated by experimental results using a redundant 7R manipulator and a mock-up conditioning tool

Automation of product packaging for industrial applications

[EN] This work presents a robotic-based solution devised to automate the product packaging in industrial environments. Although the proposed approach is illustrated for the case of the shoe industry, it applies to many other products requiring similar packaging processes. The main advantage obtained with the automated task is that productivity could be significantly increased. The key algorithms for the developed robot system are: object detection using a computer vision system; object grasping; trajectory planning with collision avoidance; and operator interaction using a force/torque sensor. All these algorithms have been experimentally tested in the laboratory to show the effectiveness and applicability of the proposed approach.This work has been partly supported by Ministerio de Economia y Competitividad of the Spanish Government [Grant No. RTC201654086 and PRI-AIBDE-2011-1219], by the Deutscher Akademischer Austauschdienst (DAAD) of the German Government (Projekt-ID 54368155) and by ROBOFOOT project [Grant No. 260159] of the European Commission.Perez-Vidal, C.; Gracia, L.; De Paco, J.; Wirkus, M.; Azorin, J.; De Gea, J. (2018). Automation of product packaging for industrial applications. International Journal of Computer Integrated Manufacturing. 31(2):129-137. https://doi.org/10.1080/0951192X.2017.1369165S12913731

Beyond the lessons learned from the COVID-19 pandemic: opportunities to optimize clinical trial implementation in oncology

COVID-19 pandemic; OncologyPandemia de COVID-19; OncologíaPandèmia de COVID-19; OncologiaIn this paper, we aim to capitalize on the lessons learnt from the impact of the COVID-19 pandemic on clinical trials and use them as a catalyst to launch a discussion over a framework of broader adaptations needed in the design and implementation of oncology clinical trialsNone declared

Biomarkers predicting the controller dose of omalizumab in patients with chronic spontaneous urticaria

Background Clinical trials showed the efficacy of 300 mg/4 weeks of omalizumab (OMA) during 6 months in patients with severe chronic spontaneous urticaria (CSU). Nevertheless, in real life, many patients require higher doses and/or longer treatment. This study assesses the real-life performance of OMA in severe CSU and identifies factors associated with the response. Methods CSU patients eligible for OMA were recruited prospectively. Clinical data and a blood test were collected before OMA initiation. Urticaria Activity Score 7 (UAS7) was calculated at baseline and every 3 months during OMA treatment. CSU control was defined as UAS7 <7 points. This work was partially sponsored by OMA manufacturer. Results Eighty-nine adults (19.1% males) with severe CSU were recruited. Median duration of CSU prior to OMA initiation was 2 years, and median severity by UAS7 at baseline was 24 points (range 10–42 points). OMA controlled 94.4% of patients, but 17.9% of responders required doses >300 mg/4 weeks. A blood basophil count >20 cells/μL (OR 13.33; 95% CI 3.32–52.63; p 29 months at the end of the study (active responders, AR). AR had received OMA for a median of 45 months (30–100 months). There were no significant differences in clinical or analytical factors between RR and AR patients. Conclusions Low blood basophil count and the presence of hypothyroidism might serve as biomarkers for the controller dose of OMA in severe CSU patients.Funding for open Access charge: Universidad de Málaga / CBUA. Instituto de Salud Carlos III; Novartis Pharmaceuticals Corporation; Consejería de Salud y Bienestar Social, Junta de Andalucí

Soluble CD137 as a dynamic biomarker to monitor agonist CD137 immunotherapies

Background On the basis of efficacy in mouse tumor models, multiple CD137 (4-1BB) agonist agents are being preclinically and clinically developed. The costimulatory molecule CD137 is inducibly expressed as a transmembrane or as a soluble protein (sCD137). Moreover, the CD137 cytoplasmic signaling domain is a key part in approved chimeric antigen receptors (CARs). Reliable pharmacodynamic biomarkers for CD137 ligation and costimulation of T cells will facilitate clinical development of CD137 agonists in the clinic. Methods We used human and mouse CD8 T cells undergoing activation to measure CD137 transcription and protein expression levels determining both the membrane-bound and soluble forms. In tumor-bearing mice plasma sCD137 concentrations were monitored on treatment with agonist anti-CD137 monoclonal antibodies (mAbs). Human CD137 knock-in mice were treated with clinical-grade agonist anti-human CD137 mAb (Urelumab). Sequential plasma samples were collected from the first patients intratumorally treated with Urelumab in the INTRUST clinical trial. Anti-mesothelin CD137-encompassing CAR-transduced T cells were stimulated with mesothelin coated microbeads. sCD137 was measured by sandwich ELISA and Luminex. Flow cytometry was used to monitor CD137 surface expression. Results CD137 costimulation upregulates transcription and protein expression of CD137 itself including sCD137 in human and mouse CD8 T cells. Immunotherapy with anti-CD137 agonist mAb resulted in increased plasma sCD137 in mice bearing syngeneic tumors. sCD137 induction is also observed in human CD137 knock-in mice treated with Urelumab and in mice transiently humanized with T cells undergoing CD137 costimulation inside subcutaneously implanted Matrigel plugs. The CD137 signaling domain-containing CAR T cells readily released sCD137 and acquired CD137 surface expression on antigen recognition. Patients treated intratumorally with low dose Urelumab showed increased plasma concentrations of sCD137. Conclusion sCD137 in plasma and CD137 surface expression can be used as quantitative parameters dynamically reflecting therapeutic costimulatory activity elicited by agonist CD137-targeted agents

The immunotherapy potential of agonistic anti-CD137 (4-1BB) monoclonal antibodies for malignancies and chronic viral diseases

Pharmacological intervention on the immune system to achieve more intense lymphocyte responses has potential application in tumour immunology and in the treatment of chronic viral diseases. Immunostimulating monoclonal antibodies are defined as a new family of drugs that augment cellular immune responses. They interact as artificial ligands with functional proteins of the immune system, either activating or inhibiting their functions. There are humanized monoclonal antibodies directed to the inhibitory receptor CD152 (CTLA-4) that are being tested in clinical trials with evidence of antitumoural activity. As a drawback, anti-CTLA-4 monoclonal antibodies induce severe autoimmunity reactions in a fraction of the patients. Anti-CD137 monoclonal antibodies have the ability to induce potent immune responses mainly mediated by cytotoxic lymphocytes with the result of frequent complete tumour eradications in mice. Comparative studies in experimental models indicate that the antitumour activity of anti-CD137 monoclonal antibodies is superior to that of anti-CD152. CD137 (4-1BB) is a leukocyte differentiation antigen selectively expressed on the surface of activated T and NK lymphocytes, as well as on dendritic cells. Monoclonal antibodies acting as artificial stimulatory ligands of this receptor (anti-CD137 agonist antibodies) enhance cellular antitumoural and antiviral immunity in a variety of mouse models. Paradoxically, anti-CD137 monoclonal antibodies are therapeutic or preventive in the course of model autoimmune diseases in mice. In light of these experimental results, a number of research groups have humanized antibodies against human CD137 and early clinical trials are about to start

A randomized phase II clinical trial of dendritic cell vaccination following complete resection of colon cancer liver metastasis

Surgically resectable synchronic and metachronic liver metastases of colon cancer have high risk of relapse in spite of standard-of-care neoadjuvant and adjuvant chemotherapy regimens. Dendritic cell vaccines loaded with autologous tumor lysates were tested for their potential to avoid or delay disease relapses (NCT01348256). Patients with surgically amenable liver metastasis of colon adenocarcinoma (n = 19) were included and underwent neoadjuvant chemotherapy, surgery and adjuvant chemotherapy. Fifteen patients with disease-free resection margins were randomized 1:1 to receive two courses of four daily doses of dendritic cell intradermal vaccinations versus observation. The trial had been originally designed to include 56 patients but was curtailed due to budgetary restrictions. Follow-up of the patients indicates a clear tendency to fewer and later relapses in the vaccine arm (median disease free survival –DFS-) 25.26 months, 95% CI 8. 74-n.r) versus observation arm (median DFS 9.53 months, 95% CI 5.32–18.88)

CD137 (4-1BB) requires physically associated cIAPs for signal transduction and antitumor effects

CD137 (4-1BB) is a member of the TNFR family that mediates potent T cell costimulatory signals upon ligation by CD137L or agonist monoclonal antibodies (mAbs). CD137 agonists attain immunotherapeutic antitumor effects in cancer mouse models, and multiple agents of this kind are undergoing clinical trials. We show that cIAP1 and cIAP2 are physically associated with the CD137 signaling complex. Moreover, cIAPs are required for CD137 signaling toward the NF-κB and MAPK pathways and for costimulation of human and mouse T lymphocytes. Functional evidence was substantiated with SMAC mimetics that trigger cIAP degradation and by transfecting cIAP dominant-negative variants. Antitumor effects of agonist anti-CD137 mAbs are critically dependent on the integrity of cIAPs in cancer mouse models, and cIAPs are also required for signaling from CARs encompassing CD137’s cytoplasmic tail.I.M. has been granted with PID2020-112892RB funded by MICIN/AEI/10.13039/501100011033 and SAF2017-83267-C2-1-R funded by MICIN/AEI/10.13039/501100011033/ and by FEDER “Una manera de hacer Europa,” (HR21-00083) the Fundación La Caixa, “MINCITH. Metabolic requirements for immune INfiltration in effective Cancer ImmunoTHerapy” “AYUDAS FUNDACIÓN BBVA A EQUIPOS DE INVESTIGACIÓN CIENTÍFICA 2019” Fundación BBVA, the Instituto de Salud Carlos III (PI20/00002 and PI19/01128), cofinanced by the Fondos FEDER “A way to make Europe” and Joint Translational Call for Proposals 2015 (JTC 2015), TRANSCAN456 2 (code TRS-2016-00000371), and the Gobierno de Navarra Proyecto LINTERNA (reference 0011-1411-2020-000075). Funding was also received from B. J. Baselga (Fundación FERO) and the T2-EVOLVE project from the EU. I.M. and M.A. receive grant funding from Pharmamar and Highlight Therapeutics. M.A. is supported by AECC (INVES1904ALVA). J.M.Z. has been granted with PID2019-110405RB-I00 funded by MICIN/AEI/10.13039/501100011033 and with P2022/BMD-7225 funded by Consortium in Biomedicine of Comunidad de Madrid.Peer reviewe

Carcinoma-derived interleukin-8 disorients dendritic cell migration without impairing T-cell stimulation

BACKGROUND: Interleukin-8 (IL-8, CXCL8) is readily produced by human malignant cells. Dendritic cells (DC) both produce IL-8 and express the IL-8 functional receptors CXCR1 and CXCR2. Most human colon carcinomas produce IL-8. IL-8 importance in malignancies has been ascribed to angiogenesis promotion. PRINCIPAL FINDINGS: IL-8 effects on human monocyte-derived DC biology were explored upon DC exposure to recombinant IL-8 and with the help of an IL-8 neutralizing mAb. In vivo experiments were performed in immunodeficient mice xenografted with IL-8-producing human colon carcinomas and comparatively with cell lines that do not produce IL-8. Allogenic T lymphocyte stimulation by DC was explored under the influence of IL-8. DC and neutrophil chemotaxis were measured by transwell-migration assays. Sera from tumor-xenografted mice contained increasing concentrations of IL-8 as the tumors progress. IL-8 production by carcinoma cells can be modulated by low doses of cyclophosphamide at the transcription level. If human DC are injected into HT29 or CaCo2 xenografted tumors, DC are retained intratumorally in an IL-8-dependent fashion. However, IL-8 did not modify the ability of DC to stimulate T cells. Interestingly, pre-exposure of DC to IL-8 desensitizes such cells for IL-8-mediated in vitro or in vivo chemoattraction. Thereby DC become disoriented to subsequently follow IL-8 chemotactic gradients towards malignant or inflamed tissue. CONCLUSIONS: IL-8 as produced by carcinoma cells changes DC migration cues, without directly interfering with DC-mediated T-cell stimulation