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The manufacturing industry has identified a new megatrend of mass customization, which is one of the essential goals of Industry 4.0. This megatrend requires the realization of manufacturing that can respond quickly and flexibly to various changing production requirements and ensure the achievement of various quality criteria. However, the manufacturing cannot be realized by conventional manufacturing systems in which reconfigurations need to be performed by skilled engineers. This paper proposes a new reconfigurable manufacturing system concept based on an ultra-flexible transfer system. Particularly, an autonomous mobile robotic manipulator, consisting of a high-performance automated guided vehicle module and a collaborative robotic manipulator module, represents a key component of the system concept. In this context, the focus is on the cooperative control between the modules of the autonomous mobile manipulator, which is essential for high-precision processes (e.g., machining, assembly, measurement, inspection), and its wide operating area. The experimental results confirm that the proposed cooperative control improves the positioning performance of the autonomous mobile manipulator, including the time required for positioning and the positioning accuracy. [ABSTRACT FROM AUTHOR]

Sphingosine 1-phosphate receptor 1 (S1PR1), a G protein-coupled receptor, is required for lymphocyte trafficking, and is a promising therapeutic target in inflammatory diseases. Here, we synthesize a competitive S1PR1 antagonist, KSI-6666, that effectively suppresses pathogenic inflammation. Metadynamics simulations suggest that the interaction of KSI-6666 with a methionine residue Met124 in the ligand-binding pocket of S1PR1 may inhibit the dissociation of KSI-6666 from S1PR1. Consistently, in vitro functional and mutational analyses reveal that KSI-6666 causes pseudoirreversible inhibition of S1PR1, dependent on the Met124 of the protein and substituents on the distal benzene ring of KSI-6666. Moreover, in vivo study suggests that this pseudoirreversible inhibition is responsible for the persistent activity of KSI-6666., (© 2024. The Author(s).)

A 70-year-old male patient was diagnosed with advanced gastric cancer with para-aortic lymph node metastasis. After diagnostic laparoscopy, the patient received 2 courses of neoadjuvant chemotherapy. Subsequently, distal gastrectomy, D2 plus para-aortic lymph node dissection, and Roux-en-Y reconstruction were performed. An enlarged lymph node(No. 16b2)was identified during surgery. The histopathological diagnosis revealed ypT4b, ypN3b, cM1(LYM; No. 16), Stage ⅣB. Chemotherapy with ramucirumab plus nab-paclitaxel was administered at 6 weeks postoperatively. However, after 2 courses of chemotherapy, the patient developed an abscess discharge from the wound, which was confirmed by an abdominal CT scan and diagnosed as an intra-abdominal abscess derived from duodenal perforation. The abscess was drained percutaneously. Subsequently, chemotherapy with nab-paclitaxel, nivolumab, and trifluridine/tipiracil hydrochloride was administered. After the appearance of brain metastases, the treatment was shifted to palliative care. The patient died 2 years and 7 months later from the primary disease.

Avacopan (TAVNEOS ® capsules) is an orally available selective C5a receptor (C5aR) antagonist. It has been approved in Japan since 2021 for the treatment of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA), the two major subtypes of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current standard therapy combining glucocorticoids (GC) and immunosuppressants has greatly improved the prognosis of AAV, however, issues such as side effects associated with GC use remain to be resolved. Avacopan suppresses priming of neutrophils induced by the complement component C5a, a process deeply involved in the pathogenesis of AAV. In pre-clinical studies, avacopan inhibited chemotaxis and priming of neutrophils induced by C5a-C5aR signaling. It also significantly suppressed nephritis and renal damage in an ANCA-induced glomerulonephritis mouse model. In the global phase 3 study "ADVOCATE", avacopan achieved both primary endpoints being 1) non-inferior to prednisone in inducing remission at week 26 and 2) superior in sustained remission at week 52 for MPA and GPA patients. Additionally, with avacopan, GC toxicity score was significantly lower and fewer adverse events possibly related to GC were observed. Furthermore, avacopan increased estimated glomerular filtration rate (eGFR) more than prednisone indicating improved renal function. Thus, the novel mechanism of avacopan targeting the complement system is a promising new therapeutic option for AAV with fewer GC-related side effects and better improvement of renal function.